To explore the MRI T2 fluid-attenuated inversion recovery (FLAIR) vascular hyperintensities (FVH) combined with diffusion-weighted imaging (DWI) Alberta Stroke Program Early CT Score (ASPECTS) in predicting the prognosis of acute cerebral infarction (ACI) with endovascular treatment.The patients with ACI in the anterior circulation who underwent endovascular treatment from June 2016 to December 2020 were divided into a good prognosis group and a poor prognosis group according to the modified Rankin Scale (mRS) score at 90 days after the operation. The differences in general clinical baseline data, CT-ASPECTS, FVH, and DWI-ASPECTS between the two groups were analyzed. The receiver operating characteristic (ROC) curve was used to analyze the predictive power of prediction models on prognosis.The results of the Binomial Logistic regression equation showed initial National Institute of Health stroke scale (NIHSS), Mori grade, DWI-ASPECTS, and FVH were independent risk factors for prognosis. The predictive power of the FVH + DWI-ASPECTS prediction model was highest, and the predictive power of DWI-ASPECTS was higher than that of CT-ASPECTS.DWI-ASPECTS is better than CT-ASPECTS in predicting the prognosis of ACI with endovascular treatment, and the combined prediction model of FVH and DWI-ASPECTS has higher prediction performance, which can be used as a preoperative evaluation method to predict the effect of endovascular treatment for ACI. The maiWith the development of imaging technology, more and more studies have shown that some imaging indicators can predict the prognosis of ACI with endovascular treatment. Several CT and MRI parameters are considered to be risk indicators for patients with ACI after endovascular therapy , 5. AlbeThis study aimed to compare and analyze the predictive power of CT scan ASPECTS score and DWI ASPECTS score on prognosis, and to explore the value of FVH combined with DWI ASPECTS score in predicting the prognosis of ACI with endovascular treatment.22.1Sixty-five patients with ACI in the anterior circulation who underwent endovascular treatment in the Department of Neurology of our hospitals from June 2016 to December 2020 were selected as the research objects. Inclusion criteria: ① Age ≥ 18 years old; ② within the 24 h interval between symptom onset and operation; ③ ASPECTS ≥ 6; ④ National Institute of Health stroke scale, (NIHSS) ≥ 6; ⑤ No operation contraindications.This study was approved by the ethics committee of the Second People’s Hospital of Lianyungang (2015 x 033). Due to the retrospective nature of the study, informed consent was waived.2.2This study was a retrospective analysis of the data collected from the hospital. All patients were confirmed with anterior circulation great vessel occlusion by MRA. The endovascular treatment was performed according to the hospital’s protocol. Sixty-five patients were divided into a good prognosis group  and a poor prognosis group  according to the mRS at 90 days after the operation.2.3The clinical data analyzed in this study included: age, gender, high blood pressure (HBP) history, diabetes mellitus (DM) history, atrial fibrillation onset (AF) history, onset to reperfusion time, stroke classification  , FVH, in2.4Baseline CT image or DWI was used to grade the ASPECTS  standardSIMENS spectra HD x 3.0T MR scanner with an 8-channel cranial phased array coil was used for detection. The scan range was from the lower end of the medulla oblongata to the top of the skull. T2-FLAIR sequence: TR 85 00.0 ms, TE 145.0 ms, FOV 240 mm × 240 mm, matrix 320 × 224, NAX 1, layer thickness 6 mm, spacing 1 mm.The Olindo scoring method was used to evaluate the FVH . Scoring1).A 67-year-old female patient was admitted to the hospital because she was “discovered with weakness in her left limb for 3.5 hours”. MRA indicated occlusion of the right middle cerebral artery. The CT-ASPECT score was 7 points, and the DWI-ASPECT score was 5 points, suggesting that the DWI-ASPECT score could better reflect the situation of the infarct. The FVH score was 5 points, which indicated the existence of collateral circulation. After intra-arterial thrombus removal, the patient’s NIHSS score dropped from 23 to 11 points  curve was used to analyze the predictive power on prognosis, and the area under the ROC curve (AUC) was compared with the DeLong test. 33.1p < 0.05). There was no statistically significant difference in other baseline data between groups (p > 0.05). The results were shown in (Table 1).The age, CT-ASPECTS, DWI- ASPECTS of the good prognosis group were higher than that of the poor prognosis group, the NIHSS of the good prognosis group was lower than that of the poor prognosis group, the FVH score ofthe good prognosis group was higher than that of poor prognosis group, and the differences between groups were statistically significant (3.22).Substituting factors such as age, Initial NIHSS or CT-ASPECTS, DWI- ASPECTS, Mori grade, and FVH were taken into the Binomial Logistic regression equation. The results of the Binomial Logistic regression equation showed initial NIHSS , Mori grade , DWI- ASPECTS , FVH  were independent risk factors for prognosis. The results are shown in (Table 3.3p < 0.05) .The ROC curve was used to analyze the predictive power of CT-ASPECTS, DWI-ASPECTS, and FVH + DWI-ASPECTS prediction model on prognosis. The results showed the area under curve (AUC) of CT-ASPECTS, DWI-ASPECTS and FVH + DWI-ASPECTS prediction model on prognosis were 0.724 (95%CI: 0.599-0.82), 0.810 (95%CI: 0.693-0.896), 0.915 (0.820-0.970) respectively. The predictive power of the FVH + DWI-ASPECTS prediction model was highest, and the predictive power of DWI-ASPECTS was higher than that of CT-ASPECTS, and the differences between groups were statistically significant (4Cerebral infarction refers to the blood supply disorder of the brain caused by various reasons, leading to ischemia and hypoxic necrosis of brain tissue. It is a common disease that seriously endangers human health. Cerebral infarction and cerebral hemorrhage are collectively referred to as a stroke, the fatality rate ranks second among all diseases in the world, and it is the primary cause of disability . EndovasThis study firstly analyzed the clinical baseline data of the two groups, the results showed patients in the good prognosis group were younger and had a better neurological function, collateral circulation, and ASPECTS on admission, and vascular recanalization was better, which was basically consistent with the other researches -17. ThenIn summary, DWI-ASPECTS is better than CT-ASPECTS in predicting the prognosis of ACI with endovascular treatment, and the combined prediction model of FVH and DWI-ASPECTS has higher prediction performance, which may be used as a preoperative evaluation method to predict the effect of endovascular treatment for ACI.


HPV‐related oropharyngeal squamous cell carcinoma (OPSCC) is associated with a favorable prognosis, yet patients of color and low socioeconomic status (SES) continue to experience inferior outcomes. We aim to understand how the emergence of HPV has impacted race and SES survival disparities in OPSCC.A retrospective cohort of 18,362 OPSCC cases from 2010 to 2017 was assembled using the SEER  database. Cox proportional regression and Fine and Gray regression models were used to calculate hazard ratios (HRs) adjusting for race, SES, age, subsite, stage, and treatment.Black patients had lower overall survival than patients of other races in HPV‐positive and HPV‐negative OPSCC . Higher SES was associated with improved survival in all patients. Race had a diminished association with survival among high SES patients. Low SES Black patients had considerably worse survival than low SES patients of other races.Race and SES interact variably across cohorts. High SES was protective of the negative effects of race, although there remains a disparity in outcomes among Black and non‐Black patients, even in high SES populations. The persistence of survival disparities suggests that the HPV epidemic has not improved outcomes equally across all demographic groups. The epidemic of HPV‐related oropharyngeal squamous cell carcinoma (OPSCC) has remarkably changed the landscape of head and neck squamous cell carcinoma with the potential to improve outcomes and decrease treatment morbidity uniformly across demographic groups. This study evaluated the combined influence of race and socioeconomic status (SES) on OPSCC survival stratified by HPV status. Survival disparities between patients of high and low SES census tracts and Black and White race remained despite the increase in HPV‐related disease. Black patients with OPSCC had lower survival than patients of other races regardless of HPV status. High SES was protective of the adverse effects of race, although there remains a disparity in outcomes among Black and non‐Black patients, even in high SES populations. We speculate that the intersection of race and neighborhood SES are critical prognostic factors even when stratifying by HPV status. We hypothesize that the survival disparities between patients of (1) high and low SES census tracts and (2) Black and White race remain despite the increase in HPV‐related disease.22.1The SEER  18 Census Tract‐level SES and Rurality Database (2000–2015) of the National Cancer Institute was utilized to assemble a retrospective cohort of OPSCC cases diagnosed between 2010 and 2017. OPSCC cases were defined using the following International Classification of Disease for Oncology (ICD‐O‐3) site codes: base of tongue , tonsil , and oropharynx . Cases were classified as HPV positive, HPV negative, or unknown/NA. HPV status was determined by positive in situ hybridization for high‐risk HPV  and/or positive p16 staining by immunohistochemistry. Only cases with squamous cell histology were included .2.2Cases were grouped into HPV‐positive and HPV‐negative cohorts. Cases with unknown/NA HPV status were excluded in the survival analyses. The primary exposures of interest were race and SES. Other variables of interest included age, sex, year of diagnosis, primary subsite , stage, treatment, and rural–urban context. All covariate variables were available through SEER.Race was defined as non‐Hispanic White, non‐Hispanic Black, non‐Hispanic Asian American or Pacific Islander, or Hispanic . SES quintiles were available in SEER, with the first quintile representing the lowest SES group and the fifth quintile representing the highest SES group. These quintiles were generated using a SES index constructed from a factor analysis of seven census tract variables  and linked to tumor cases at the census tract level based on diagnosis year.2.3The primary outcome was overall survival (OS), which was defined as duration from diagnosis date to death from any cause provided by SEER. The secondary outcome was cancer‐specific survival (CSS), which was defined as duration from diagnosis date to OPSCC‐related death. We censored patients after 5 years from diagnosis date.2.4t‐tests, chi‐square, or exact tests where appropriate. p < 0.05 was considered statistically significant. Univariate survival analysis was performed with Kaplan–Meier curves and log‐rank tests. Restricted mean survival time (RMST) was estimated as an alternative measure of survival. RMST can be interpreted as the “life expectancy” between diagnosis and our chosen time horizon of 5 years, with the change in RMST (ΔRMST) representing the difference in “life expectancy” between two groups of interest.survival (3.2–7) and survminer (0.4.8) R packages were used for survival analysis.Descriptive statistics were calculated with 33.1n = 11,552, 86.6% vs. n = 3782, 75.4%). The number of HPV‐positive OPSCC cases, as well as the proportion of OPSCC cases that were HPV‐positive, diagnosed each year trended upward from 2010 to 2017. HPV‐positive patients were more likely to be White than HPV‐negative patients . Likewise, Hispanic, Asian American or Pacific Islander (AAPI), and Black patients comprised a larger proportion of HPV‐negative patients than HPV‐positive patients. We noted a trend of higher SES among HPV‐positive patients, with HPV‐positive patients more likely to be in the highest quintile for SES than their HPV‐negative counterparts .In total, 18,362 OPSCC patients had HPV status and were included in the analysis  ; investigation ; visualization ; writing – original draft (lead); writing – review and editing (lead). Benjamin M. Wahle: Conceptualization ; visualization ; writing – review and editing . Sean T. Massa: Conceptualization ; methodology ; writing – review and editing . Paul Zolkind: Writing – review and editing . Randal C Paniello: Writing – review and editing . Patrik Pipkorn: Writing – review and editing . Ryan Jackson: Writing – review and editing . Jason T Rich: Writing – review and editing . Sid Puram: Conceptualization ; methodology ; project administration ; supervision ; writing – review and editing . Angela Liu Mazul: Conceptualization ; data curation ; formal analysis ; investigation ; methodology ; project administration ; supervision ; visualization ; writing – review and editing .ALM is supported by the National Institute of Minority Health and Health Disparities (K01MD013897). BMW is supported by the National Institute of Deafness and Other Communication Disorders within the National Institutes of Health, through the “Development of Clinician/Researchers in Academic ENT” training grant (T32DC000022). ALM and SVP are supported by the Barnes Jewish Foundation. The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health.None.Table S1–S2.Click here for additional data file.


LGSI was defined as hs-CRP ≥ 2 and <10 mg/L, and its associations with socio-demographic, lifestyle, and cardiometabolic characteristics were analyzed. The prevalence of LGSI (age-standardized to European Standard Population 2013) was 34.1% (33.5% in men and 36.1% in women). In the total sample, the increased odds ratios (ORs) of LGSI were associated with abdominal obesity (2.1), smoking (1.9), dyslipidemia (1.5), pulmonary diseases (1.4), and hypertension (1.3); the decreased ORs were in women (0.6) and in married participants (0.6). In men, the ORs were higher with abdominal obesity (2.1), smoking (2.0), CVDs (1.5), and hazardous drinking (1.5); in women—with abdominal obesity (4.4) and pulmonary diseases (1.5). In conclusion, one-third of the adult population in Arkhangelsk had LGSI. Abdominal obesity was the strongest LGSI correlate in both sexes, while the profiles of other associated factors were different between men and women.Mortality from cardiovascular diseases (CVDs) is higher in Russia compared to other European countries. High-sensitivity C-reactive protein (hs-CRP) is a biomarker of inflammation, and its elevated levels indicate increased CVD risks. We aim to describe the prevalence of low-grade systemic inflammation (LGSI) and the associated factors in a Russian population. The Know Your Heart cross-sectional study was conducted in Arkhangelsk, Russia in 2015–2017 with a population sample aged 35–69 years ( C-reactive protein (CRP) is a biomarker of inflammation ,2,3. HigMortality from CVDs in Russia exceeds that in the majority of European countries, especially among middle-aged men . The KnoThe elevated levels of inflammation in Russia may also be due to specific socio-economic and lifestyle characteristics ,22,23,24Based on the weaknesses of the existing explanations of the earlier observed elevated levels of inflammation in Russia’s population, the aim of our study is to describe the distribution of LGSI in the adult population of Arkhangelsk, Russia and investigate its socio-demographic, lifestyle, and cardiometabolic correlates.https://knowyourheart.science/; accessed on 8 May 2023). In Arkhangelsk, the KYH study population comprised men and women aged 35–69 years (n = 2380), randomly sampled from the general population, and representing 1.5% of the total residents in the age span. The participants were sampled using the depersonalized database of the Arkhangelsk territorial health insurance fund, containing information about all residents with mandatory health insurance. The dataset accessed for the sampling purposes contained anonymous addresses of the insured residents aged 35–69 years, supplemented by age and sex variables. Trained interviewers visited randomly selected addresses. When a contact at an address was made, a household member of the defined age (±2 years) and sex was invited to take part in the study. Among the invited, 68% agreed and had an interview at home. The interview participates were offered a health examination at the polyclinic of the Northern State Medical University, and 96% underwent the examination. Details of the KYH study rationale, design, sampling, recruitment, and measurement procedures were published earlier [We used data from the Know Your Heart (KYH) cross-sectional study of cardiovascular diseases, which was conducted in Arkhangelsk and Novosibirsk in 2015–2018 as a part of the international project on cardiovascular disease in Russia (Trained interviewers conducted at-home (baseline) interviews and collected data on participants’ demographic, socio-economic, and lifestyle characteristics, self-reported diseases, and use of healthcare services. Trained physicians and nurses conducted medical examinations at the polyclinic, including a medical interview , taking blood samples, and a series of instrumental and functional measurements of cardiovascular health and related parameters. The participants were asked to fast for four hours prior to the examination; therefore, blood samples were taken in four or more hours after the last meal. The samples were centrifuged with the serum frozen at −80 °C. When the fieldwork was finished, the samples were analyzed in a single batch.n = 10) were excluded from all analyses. The participants with hs-CRP ≥ 2 mg/L and <10 mg/L were categorized as LGSI-positives (LGSI+), and those with hs-CRP < 2 mg/L were treated as LGSI-negatives (LGSI-). The participants with hs-CRP ≥ 10 mg/L, which was considered an indication of an acute inflammatory process, were included when assessing hs-CRP levels and the LGSI prevalence in the studied population, but were excluded from analyses of LGSI associations with socio-economic, lifestyle, and cardiometabolic characteristics.LGSI was defined based on the serum level of hs-CRP, measured using immuno-turbidimetric test . The participants with missing hs-CRP data , sex (man or woman), marital status , higher education (yes or no), poor financial situation . In addition, occupation was analyzed as having regular paid work (yes or no) and as four occupation categories according to the International Standard Classification of Occupation (ISCO) : high-sk2).To assess LGSI associations with living conditions, we used data on participants’ housing characteristics , household size (number of people living together), and dwelling size (size of apartment or house) per one household member . Hazardous drinking was defined as a score ≥8 on the Alcohol Use Disorders Identification Test (AUDIT) . PhysicaCardiometabolic correlates of LGSI and hs-CRP levels were analyzed at several levels, starting with directly measurable blood biomarkers and instrumentally measured body parameters, proceeding to composite conditions , and ending with diagnosed diseases.est) was calculated using Friedewald equation (LDL-Cest = TC − (HDL-C + TG/2.2)) [est from TC. If TG levels were >4 mmol/l, directly measured LDL-C values were used in the formulae.Levels of TC (mmol/L), HDL-C (mmol/L), LDL-C (mmol/L), and triglycerides (TG) (mmol/L) were assessed in the blood serum using enzymatic color tests; apolipoprotein A-I (Apo A1) (g/L), apolipoprotein B (Apo B) (g/L), and glycated hemoglobin (HbA1c) (%)—using immuno-turbidimetric tests, lipoprotein(a) (Lp(a)) (mg/dl)—using a particle-enhanced immuno-turbidimetric test  . Apo B/ATG/2.2)) , and theSystolic and diastolic blood pressure (SBP and DBP) (mm Hg) were measured on the brachial artery using an OMRON 705 IT automatic blood pressure monitor . The measurements were performed three times at two-minute intervals. SBP and DBP were analyzed as means of the second and third measurements.® 217 stadiometer . Weight (kg) was measured using TANITA BC 418 body composition analyzer . Waist circumference (WC) (cm) and hip circumference (HC) (cm) were measured using Seca® 201 measuring tape (Seca Limited). WC was measured at the narrowest part of the trunk. Height, WC, and HC were measured twice, and the averages of the two measurements were used in the analysis. Body mass index (BMI) was calculated as weight in kilograms divided by squared height in meters. Waist-to-hips ratio (WHR) was calculated as WC divided by HC. Abdominal obesity was defined as WC > 94 cm for men, or > 80 cm for women.Height (cm) was measured using a SecaMedication data were collected by asking the participants about their currently used medicines. The commercial name, dose, indication, and frequency were recorded for up to seven medications. The recorded medications’ names were coded using the international WHO anatomical therapeutic chemical (ATC) classification system version 2016 ,37. LipiDyslipidemia was defined as TC ≥ 5.2 mmol/L and/or TG > 1.7 mmol/L and/or LDL-C > 3.0 and/or HDL-C < 1.0 mmol/L for men and/or HDL-C < 1.2 mmol/L for women and/or intake of lipid lowering medication. Hypertension was defined as SBP > 140 mm Hg and/or DBP > 90 mm Hg and/or self-reported intake of antihypertensives. Diabetes was defined as HbA1c ≥ 6.5% and/or self-reported intake of antidiabetics and/or self-report of having been diagnosed with diabetes, followed by the statement of the diabetes type and the treatment prescribed .According to the AHA/NHBLI (2009) criteria, metabolic syndrome (MS) was defined  as havinData on the history of diseases were collected by asking the participants about having ever been diagnosed with a CVD , a pulmonary disease , a joint disease , diabetes mellitus, cancer, a kidney disease, or a liver disease. In addition, we used answers to questions about a prior heart surgery (percutaneous coronary intervention or coronary bypass surgery) and clarifying questions to the participants who self-reported diabetes . The listed diseases were considered present if the corresponding diagnoses were self-reported.Depression was measured using the patient health questionnaire-9 (PHQ-9), and the cut point of ≥5 was used to define any depression  . The anxAnalyses of hs-CRP population levels and the LGSI prevalence were performed on the sample of 2370 KYH participants, after excluding 10 KYH participants with missing hs-CRP data. Further analyses of LGSI correlates were performed on the sample of 2054 participants, after exclusions of 158 participants with hs-CRP concentration > 10 mg/L, 61 participants who self-reported taking anti-inflammatory medication, and 97 participants with missing data on any of the analyzed variables.Absolute numbers (Abs) and proportions (%) were used to present categorical variables. Proportions representing prevalence estimates were shown with 95% confidence intervals (CIs). Age-standardized proportions were calculated based on the European Standard Population 2013 in the age span of 35–69 years, with 5-year intervals. Mean values (Ms) with standard deviations (SDs) and/or medians (Mes) with quartiles  were used to present continuous and count variables. In selected analyses, skewed continuous variables were included in ln-transformed form and presented as geometric means.Analyses of LGSI associations with socio-demographic, lifestyle, and cardiometabolic characteristics were performed stratified by sex and on the pooled sample with significant interactions between sex and other socio-demographic, lifestyle, and cardiometabolic covariates considered. For each covariate, interaction with sex was assessed by comparing regression models with and without the interaction term using the likelihood ratio test.Comparisons of the LGSI-positive and LGSI-negative participants on categorical variables were made using Pearson’s chi-squared test and Cochran–Armitage test for trend where relevant. Differences between the two groups on normally distributed continuous variables were assessed using a two-sample t-test on continuous variables with skewed distributions and on count variables—using two-sample Wilcoxon rank-sum test and Jonckheere–Terpstra test for trends where relevant. Parameters that differed between the LGSI-positive and LGSI-negative participants in men and/or in women were entered into further multivariable analyses of the associations with LGSI.The LGSI associations with socio-demographic, lifestyle, and cardiometabolic characteristics were assessed using multivariable logistics regressions with stepwise entry of covariates. First, LGSI associations with all studied parameters, except age, were adjusted for age (Model 1). Second, socio-demographic and lifestyle variables  were mutually adjusted, with the addition of significant interaction terms sex by being married and sex by smoking (Model 2). Next, we added cardiometabolic conditions  and interaction term sex by abdominal obesity (Model 3). Finally, we added self-reported diseases  (Model 4). Based on the identified interactions of several variables with sex, the same analyses were repeated for men and women separately. Additionally, analyses of the earlier identified independent correlates of LGSI were repeated with MS variable entered instead of a set of previously used cardiometabolic conditions (separate MS components). This was performed on the total sample using multivariable logistic regression with all variables mutually adjusted and added interaction terms sex by marital status and sex by smoking. To address the identified interactions, these analyses were also performed stratified by sex. Results of these analyses were presented as adjusted odds ratios (ORs) with 95% CIs.The strength of the associations between the hs-CRP level and cardiometabolic biomarkers, which are conventionally assessed at a screening or a doctor visit , was assessed using multivariable linear regressions with the ln-transformed hs-CRP level as the dependent variable and with adjustment for age and sex. Results of these analyses are presented as standardized β coefficients, which allow comparing the strengths of the discovered associations.All analyses were performed using STATA V.17 .n = 2370) comprised 987 men (41.6%) and 1383 women (58.4%). The mean age was 53.8 years, equal for men and women. The median hs-CRP levels were 1.59  mg/L in the total (pooled) study population, 1.65  mg/L in men, and 1.50  mg/L in women. The median hs-CRP levels increased with age in both sexes (p = 0.012).The studied population (th sexes . The geon = 830) constituted 35.0%  of the total study population, 33.5%  of men (n = 331), and 36.1  of women (n = 499) (p = 0.200). Age-standardized to the European Standard Population 2013, the proportion of the participants with LGSI was 34.1%  for the total study population, 32.7%  for men, and 35.1  for women. The proportions of LGSI-positive participants were growing with age in both men and women  , increasSex had no associations with LGSI after the adjustment for age Model 1, . The samThe participants with higher education had reduced odds of LGSI in the pooled analysis after the adjustment for age (Model 1), but not after the following adjustments for other socio-demographic and lifestyle variables  , but not after adjustments for other socio-demographic and lifestyle variables   . The ass= 0.027) .Hazardous drinking was associated with increased odds of LGSI in the pooled age-adjusted model and after adjustments for socio-demographic characteristics and smoking (Models 1–2), but not after further adjustments for cardiometabolic characteristics and self-reported diseases , but not after the following adjustments . The samp < 0.001) between abdominal obesity and sex in the pooled analysis , but not after the adjustment for all other studied variables Model 4, . Men witPulmonary diseases were associated with increased odds of LGSI in the pooled analysis, both after age-adjustment (Model 1) and after all the following adjustments Model 4, . Women wJoint diseases were associated with increased odds of LGSI in the pooled analysis after the adjustment for age (Model 1), but not after the adjustment for all other studied variables Model 4, . In the In the pooled analyses, hs-CRP levels were higher with higher values of TC, LDL-C, TG, non-HDL cholesterol, remnant cholesterol, Apo B, and Apo B/Apo A-1 ratio, SBP and DBP, HbA1c, BMI, WC, HC, WHR, and antihypertensive and antidiabetic medication . The hs-Among the blood lipids, the strongest correlates of hs-CRP were TG (β = 0.265), remnant cholesterol (β = 0.247), and Apo B/Apo A-1 ratio (β = 0.226) . These pDBP had a slightly stronger association with the hs-CRP level compared to SBP in the pooled analysis (β = 0.198 vs. β = 0.174) . The difIn the pooled analysis, HbA1c had a modest association with hs-CRP (β = 0.149) compared to other hs-CRP correlates , and agaAmong all the cardiometabolic biomarkers in the study, anthropometric parameters had the strongest positive associations with hs-CRP . WHR wasBeing markers of hypertension and diabetes under treatment, self-reports of taking antihypertensives and antidiabetics also showed associations with increased hs-CRP levels in the pooled analyses  . In the We described the distribution of LGSI in adult men and women of Arkhangelsk, Russia and identified the associated characteristics. The study contributed to the knowledge of systemic inflammation and associated factors, predictors and consequences, generated by the earlier studies in Russian populations ,42,43,44Population levels of hs-CRP  in Arkhangelsk adult population aged 35–69 years were within the spectrum of earlier estimates for white or European populations ,45,46. TOur study demonstrated that hs-CRP levels increased with age, which is consistent with findings of other studies ,47,48,49The median level and the geometric mean of hs-CRP were higher in men, while the prevalence of LGSI had no significant difference between sexes. Previous research showed higher levels of CRP in men  and no sDespite no sex difference in the LGSI prevalence, sex showed interactions with marital status, smoking, and abdominal obesity in its associations with LGSI. Adjustments for these interactions resulted in reduced odds of LGSI in women, reflecting that the association between sex and LGSI depends on having the interacting factors. The sex-stratified analysis allowed describing the nature of these interactions. Based on the discovered age-adjusted associations, a man with LGSI at a screening in Arkhangelsk would most likely be of an older age, unmarried, not in regular paid work, a smoker, and a hazardous drinker. He would likely have abdominal obesity, hypertension, dyslipidemia, and a CVD in anamnesis. For comparison, woman with LGSI would likely have an older age, no higher education, no regular paid work, and would likely be a high-skilled blue-collar. She would likely have cardiometabolic conditions , pulmonary diseases, and joint diseases. However, when the associations with LGSI were assessed with socio-demographic variables, lifestyle variables, and cardiometabolic conditions mutually adjusted, older age, higher education, being in regular paid work, and being a blue-collar were no longer significant LGSI correlates in the pooled and sex-stratified analyses. Therefore, the associations of these socio-demographic characteristics with LGSI were likely mediated by the studied lifestyle and cardiometabolic variables. Similarly, a number of previous studies demonstrated associations of higher CRP levels with lower levels of education and income, but health behaviors and metabolic parameters explained the major part of these differences ,63,64,65Being married was found associated with lower odds of LGSI in men, but not in women, and the association persisted all the adjustments. A difference in diet between married and unmarried men might be an explanation, but we did not see a difference between these groups in dietary quality. Another explanation might be a higher number of sexual partners and higher exposure to sexually transmitted infections among unmarried men, which could led to elevated hs-CRP levels. Alternatively, reduced levels of sex hormones among unmarried men could have led to lower testosterone levels, and these levels were shown to be associated with pro-inflammatory state . We had Smoking and hazardous drinking were more prevalent among men, and only in men, these characteristics had associations with LGSI, regardless of the adjustments. According to previous studies, the association of LGSI with smoking could be explained by the induction of local and systemic inflammation via generalized leukocytosis, platelet aggregation, and the influence on compounds of visceral adipose tissue, resulting in the release of interleukin-6 and additional CRP production in hepatic cells ,30. As fOur analyses have demonstrated LGSI associations with all four studied cardiometabolic conditions , except for diabetes in men. Out of the four, abdominal obesity had the strongest association with LGSI in both men and women, being twice as strong correlate of LGSI in women compared to men. These findings suggest that LGSI in the Russian population is most commonly obesity-dependent. Such systemic inflammation was described as developing due to the accumulation of adipose tissue in the abdominal area, which activates macrophages, endothelial dysfunction, excessive production of tumor necrosis factor α, interleukin-6 and adipocytokines, oxidative stress, and insulin resistance ,68. The We found the increased odds of LGSI with self-reported CVDs in men, but not in women. Pulmonary diseases and joint diseases were more commonly self-reported by women and were found associated with increased odds of LGSI in women, but not in men. These findings may indicate possible sex differences in organ-specific pathogenic determinants of LGSI. However, the findings are based on self-reports of diagnosed diseases, and there might be a differential bias in self-reports by men and women. Therefore, the discovered phenomenon is of interest, but its nature is not fully clear and requires further investigation using objective clinical data.In our study, the hs-CRP level showed associations with all studied lipid particles except for lipoprotein (a). The closest correlates of hs-CRP were TG, remnant cholesterol, and the apoB/ApoA ratio. An earlier study has shown that a high level of TG was the only one of the five MS components contributing to LGSI . The recThe association between inflammation and metabolic phenotypes may partly be explained by a shared genetic background ,18. To dPrevious studies have demonstrated the association of chronic inflammation with hypertension and its complications ,79,80 anIn additional analyses, we have shown that MS was associated with the increased odds of LGSI in both men and women. However, the associations between LGSI and MS were weaker in both sexes compared with respective associations between LGSI and abdominal obesity—an MS’s component, earlier analyzed as a separate condition. These findings indicate that abdominal obesity was the major driver of the observed MS-LGSI association.This study has several limitations. The LGSI status was assessed using hs-CRP as the only one marker of inflammation measured at a single occasion. Thus, the participants with subacute resolving inflammation could be falsely classified as LGSI-positives, and that could have attenuated the studied associations. Blood sampling was not performed at full fasting. For this reason, the described levels of lipids, triglycerides in particular, could be partially affected by the recent food intake. The data about economic and lifestyle characteristics and diseases were collected using questionnaires. Self-reported questionnaires about lifestyle could be biased due to the desirability to undervalue socially unwelcomed attitudes . The sexOne-third of the adult population in Arkhangelsk had LGSI. Proportions of participants with LGSI did not differ by sex, but increased with age in both sexes. Abdominal obesity was most closely associated with LGSI both in men and in women. Apart from that, profiles of LGSI correlates were different in men and women, suggesting sex-specific features of LGSI development and health consequences.


INK4a are suggested as a surrogate marker of HPV or EBV infection in some head and neck tumors but in LSCC is still controversial. Furthermore, pRb expression may be considered an additional biomarker but it has not been clearly defined. This work aimed to compare the expression of pRb and p16INK4a as possible biomarkers in tumor tissues with and without infection by EBV or different genotypes of HPV from patients with LSCC.Laryngeal squamous cell carcinoma (LSCC) represents one of the principal tumors of the head and neck. Human papillomavirus (HPV) and Epstein–Barr virus (EBV) are considered risk factors for the development and the clinical prognosis of LSCC. High levels of p16INK4a and pRb expression was assessed by immunohistochemistry.Tumor samples from 103 patients with LSCC were previously investigated for the presence and genotypes of HPV using the INNO-LiPA line probe assay and for the infection of EBV by qPCR. p16 INK4a was positive in 55 (53.4%) and of this, 32 (56.1%) were positive for HPV whereas 11 (39.3%) were EBV positive but both without a significantly difference (p > 0.05). pRb expression was positive in 78 (75.7%) and a higher frequency of this expression was observed in HPV negative samples (87.0%) (p = 0.021) and in high-risk HPV negative samples (85.2%) (p = 0.010). No difference was observed when comparing pRb expression and EBV infection status (p > 0.05).Of the 103 tumor samples, expression of p16INK4a is not a reliable surrogate marker for identifying HPV or EBV infection in LSCC. On the other hand, most of our samples had pRb expression, which was more frequent in tumors without HPV, suggesting that pRb could indicate HPV negativity. However, more studies with a larger number of cases are required, including controls without LSCC and evaluating other molecular markers to determine the real role of p16INK4a and pRb in LSCC.Our results support the suggestion that p16 INK4a, which is essential in cell cycle progression [INK4a [INK4a expression leads to hyperphosphorylation of pRb that promotes uncontrolled cellular proliferation [INK4a expression have been suggested as a surrogate marker of HPV and EBV infection in pharyngeal, nasopharyngeal, and oropharynx tumors, whereas in laryngeal tumors are still controversial; therefore, pRb expression may be considered as an additional biomarker, particularly in tumors with infection by HPV and EBV [INK4a as possible biomarkers in tumor tissues with and without infection by EBV or different genotypes of HPV from patients with LSCC attending a third-level care referral hospital.Laryngeal squamous cell carcinoma (LSCC) is one of the most common type of head and neck cancer and, although tobacco smoking and alcohol abuse are the principal risk factors, some viral infections are implicated , 2. Humagression . Latent n [INK4a . The altferation . High le and EBV , 17–19. Formalin-fixed and paraffin-embedded (FFPE) tissue specimens from patients with LSCC were included in a retrospective study. Samples were taken from a previous study evaluating the HPV and EBV prevalence in patients with LSCC . All patTumor sections from each FFPE sample were carefully punched off and conducted to a DNA isolation using the NucleoSpin DNA FFPE . The presence and genotype of HPV were evaluated using the INNO-LiPA HPV Genotyping Kit Extra II Amp , a line probe assay designed for the identification of 32 genotypes of the HPV, including thirteen HR-HPV , six possible HR-HPV , nine LR-HPV , and other four not yet classified HPV genotypes  . To deteINK4a and pRb was performed on 5-µm-thick FFPE tissue cross-sections using the mouse and rabbit specific HRP/DAB (ABC) detection IHC kit  with the monoclonal anti-CDKN2A/p16INK4a antibody  and the monoclonal anti-Rb antibody . Hematoxylin–eosin (HE) stains were also prepared for histological evaluation of tumors. Two independent pathologists who were blinded to the clinical information and to the HPV or EBV status of the samples evaluated all the IHC and HE stains. Evaluations were made based on staining intensity as other previous reports have done. Specimens were considered positive for p16INK4a expression if they showed ≥ 75% of stained cells, whereas for pRb, ≥ 25% of stained cells were interpreted as a positive expression [Immunohistochemical (IHC) staining method for p16pression –26.2 test, and Fisher's exact test. A p value < 0.05 was considered statistically significant. All analyzes were performed using the IBM SPSS Statistics program .We used the Mann–Whitney U test, Pearson's XINK4a if ≥ 75% of tumor cells were stained and for pRb if ≥ 25% of stained cells were observed . Most samples were from men 96.1%), and tobacco smoking was common (98.0%). In contrast, alcohol intake frequency was low (6.8%). The glottis subsite was the most frequent location of tumors (49.5%). We had 57 (55.3%) tumor samples positive for HPV DNA, and 42 (40.8%) of these had at least one HR-HPV genotype. EBV DNA was present in 28 (27.2%) samples. Of these, 16 (15.5%) were in co-infection with HPV, 11 (10.7%) corresponded to co-infections with at least one HR-HPV, and 12 (11.7%) cases had only EBV infection . According to the surgical source of the sample, biopsies (64.5%) had a higher frequency of expression of this protein than laryngectomies (p = 0.009 by the Pearson's chi-squared test). Samples cataloged as Grade III by Broder's classification showed a higher frequency of p16INK4a expression (80.9%) compared with those of grade I (50.0%) and II (42.1%) (p < 0.05 by the Mann–Whitney U test). Only one of the seven alcohol consumers showed p16INK4a expression (14.3%) (p = 0.048 by the Fisher's Exact Test). No significant difference was observed when comparing p16INK4a expression with the presence of HPV or EBV (p > 0.05 by the Fisher's Exact Test). Regarding pRb expression, 78 (75.7%) samples were positive. Specimen’s obtained from biopsies (84.2%) showed a higher frequency of pRb expression than laryngectomy samples (p = 0.025 by the Pearson's chi-squared test). The frequency of pRb expression was higher in HPV negative samples (87.0%) (p = 0.021 by the Fisher's Exact Test). A higher frequency of pRb expression was also observed in the group of HR-HPV negative samples (85.2%) (p = 0.010 by the Fisher's Exact Test). No significant differences (p > 0.05) were observed in the expression of p16INK4a or pRb by age and sex of patients, laryngeal tumor subsite, and tobacco consumption habits of the patients  of 211 LSCC specimens were positive for p16INK4a [INK4a was found in 36 (51.43%) of 70 LSCC cases [INK4a might be affected by genetic or epigenetic mechanisms [INK4a is significantly reduced and hypermethylation has been shown to be a common mechanism causing this downregulation [INK4a expression. In contrast to our results, Tong and et al. found that p16INK4a expression was observed more commonly in well-differentiated samples [INK4a. Although this low number of cases precludes reliable statistical comparison, most alcohol consumers were significantly negative for p16INK4a expression (p = 0.048). Elhadj et al. found no association between alcohol consumption and p16INK4a expression when evaluating 30 alcohol-consuming patients [INK4a were also positive for HPV infection. Stephen et al. reported the expression of p16INK4a in 21 (26.0%) of 80 patients, furthermore, 12 (57.0%) of these were positive for HPV infection [INK4a expression in 8 (7.9%) of 101 cases, and only 2 (25.0%) of these were also HPV DNA positive [INK4a expression, and 14 (29.2%) of these were positive for HPV infection [INK4a expression in 18 (20.0%) of 90 cases and only 6 (33.3%) of these were also positive for DNA of HPV [INK4a and HPV infection was observed could support the suggestion that this protein may not be reliable as a surrogate marker for HPV infection [To assess the expression of p16  disease , 27–33. for LSCC , 35. In p16INK4a . Elhadj CC cases . Expresschanisms . Some stchanisms . In LSCCgulation . We founpatients . Otherwinfection . Hernandpositive . Sancheznfection . Dogantein 36 51.% of 70 Lnfection .INK4a and pRb expression have been delineated in several types of human cancers [INK4a, its inactivation results in overexpression of p16INK4a. Thus, a positive test for HPV combined with p16INK4a expression has been described as evidence of biologically relevant infection [Modifications of the p16 cancers , 46. We  cancers . Krecick cancers . Some st cancers . IHC evanfection , 51. Thenfection . Shaikh nfection . Variousnfection . In addinfection . Thus, tINK4a in half of LSCC cases, and in half of these, HPV was also detected. However, the proportion of samples with p16INK4a expression was similar between those with HPV and EBV. Although the proportion of LSCC samples with p16INK4a expression was higher than reported in several previous studies, our findings suggest little value of this marker as a reliable surrogate for identifying HPV in laryngeal cancer. On the other hand, as in previous studies, most of our LSCC samples had pRb expression, this being more frequent in tumors without the presence of HPV, even in those positive for high-risk HPV. Therefore, pRb expression seems to indicate HPV negativity, which could justify not performing other molecular tests for HPV detection in this type of cases, as previously suggested. However, further studies with a larger number of cases, including controls without laryngeal cancer, involving other tumor suppression pathways or other molecular markers, are necessary to determine the real role of p16INK4a and pRb in LSCC.We detected p16


Policy1-Cervix, a dynamic model simulating HPV transmission, natural history, vaccination, cervical screening, and diagnosis of HPV-related cancers, to estimate the impact on HPV-related cancers from disruptions to HPV vaccination in a high-income setting. A baseline scenario of no disruption to HPV vaccination was modelled, which assumed uptake of the nonavalent vaccine at the age of 12 by 82.4% of females and 75.5% of males, as is the coverage in Australia. Additional lifetime HPV-related cancer cases were calculated for three disruption scenarios affecting one birth cohort  compared to the baseline scenario: (1) 1-year delay (no doses missed); (2) 1- to 7-year delay (slow catch-up); (3) no catch-up (herd effects only). A fourth scenario assumed no catch-up HPV vaccination for two birth cohorts, that is all individuals born in 2008 and in 2009 missed vaccination (worst-case scenario). Compared to 1532 HPV-related cancer cases estimated for the baseline no disruption scenario, we found a 1-year delay could result in ≤0.3% more HPV-related cancers (n = 4) but the increase would be greater if catch-up was slower , and especially if there was no catch-up . Additional cancers for a single missed cohort were most commonly cervical  and anal cancers (16%) in females and oropharyngeal cancers in males (20%). In the worst-case scenario of two birth cohorts missing vaccination, ≤62% more HPV-related cancers would be diagnosed (n = 1892). In conclusion, providing catch-up of missed HPV vaccines is conducted, short-term delays in vaccinating adolescents are unlikely to have substantial long-term effects on cancer.COVID-19 disrupted school attendance in many countries, delaying routine adolescent vaccination against human papillomavirus (HPV) in some settings. We used  Australia was the first country to implement a fully government funded National HPV Vaccination program. Human papillomavirus (HPV) vaccination has been routinely offered through schools, to girls aged 12–13 years since 2007 and to boys aged 12–13 years since 2013. Additionally, catch-up HPV vaccination was offered to females aged 14–26 years in 2007–2009 and to males aged 14–15 years in 2013–2014. In 2018, a three-dose schedule with the quadrivalent HPV vaccine which protects against four HPV types  was replaced by a two-dose schedule with the nonavalent HPV vaccine (HPV9), protecting against an additional five oncogenic HPV types . Since 2017, free catch-up of vaccinations under the Australian National Immunization Program, including the HPV vaccine, is available to all people aged under 20 years and is administered in primary care . HPV couFollowing the World Health Organization’s declaration of the COVID-19 pandemic in March 2020, strict national- and state-level infection control measures were introduced in Australia. Social and physical restrictions affected essential health services including the delivery of school-based vaccination programmes due to school closures from imposed lockdowns in 2020 and in some states in 2021 . GloballInfection with oncogenic HPV types is a major causal factor for the development of cervical cancer and for a fraction of cancers of the anus, oropharynx, penis, vagina, and vulva . Except The aim of this study was to estimate the additional lifetime HPV-related cancer cases in men and women that could be caused by HPV vaccination delays or missed doses due to the pandemic by using a simulation model to project the long-term outcomes from different potential disruption scenarios, using Australia as an example. The study was designed prior to the emergence of actual 2020–2021 vaccination disruption data, and hence, a number of potential disruption scenarios were considered to encompass a wide range of possibilities.In the baseline scenario of no interruption to HPV vaccination, we estimate 2583 HPV-related cancer cases would be prevented in the 2008 cohort due to HPV vaccination, equating to 63% of all HPV-related cases . The firIn the main analysis, we explicitly modelled primary HPV cervical screening as also occurring in these cohorts, which would allow the cervical screening programme to compensate, to some extent, for cervical cancers not prevented via HPV vaccination. In the sensitivity analysis that used an incidence-based approach, the number of additional cervical cancer cases predicted was larger and cervical cancers would have comprised around 35% of the additional HPV-related cancer cases  . The perThis is the first study to estimate the long-term potential impact of missed HPV vaccinations across HPV-induced cancers while accounting for natural history, sexual behaviour, and herd immunity. We found that rapid catch-up of HPV vaccination in young adolescents within a year meant that even extreme disruptions where all vaccinations were delayed had a minimal long-term effect on cancer cases. A slower pace of recovery, however, or, in the worst case, missed vaccination in one or two cohorts was associated with a higher excess burden of cancers. While herd effects from vaccination still prevented close to half of HPV-related cancers, missing a single cohort entirely would result in an estimated 49% more HPV-related cancers in that cohort compared to no disruption.In Australia, initial national figures show for adolescents aged 11 to <15 years who received their first dose in 2020, 74.7% of girls and 72.6% of boys received their second dose in the same calendar year, compared to 86.2% and 84.3%, for girls and boys, respectively, in 2019 . The difIn November 2020, WHO released a global strategy calling for all countries to take action to achieve the elimination of cervical cancer as a public health problem within the next century . In the The strengths of this study include evaluating the impact of the COVID-19 pandemic across different HPV-related cancers, in both women and men and across a wide range of possibilities for vaccination disruption – two of which assumed a delay in HPV vaccination and two scenarios where the affected birth cohorts remained unvaccinated. Some limitations should also be noted. Even in the context of some cohorts missing vaccination entirely, herd effects still prevented a considerable proportion of HPV-related cancers overall; these effects would be smaller in settings with lower coverage . This isAustralia is a relatively high HPV vaccination coverage setting. Outcomes may be less favourable in a lower coverage setting, as there would be less protection from herd effects; however, the impact of disruptions might also be smaller in a setting with lower coverage, since a lower coverage programme would be less effective. Nevertheless, the finding that if catch-up is performed expeditiously then it mitigates much of the effect from vaccination delays, is likely to hold in other settings. In a previous study modelling the health impacts of HPV vaccination hesitancy in Japan from 2013 to 2019 and the potential effects of restoring coverage to 70% with catch-up vaccination in 2020 is informative as it demonstrates that multi-age HPV catch-up vaccination, such as after catastrophic falls in coverage in Japan, would be effective in mitigating the effects .Our findings provide evidence that rapid catch-up of missed HPV vaccine doses would minimize the long-term impact of vaccination programme disruptions, but delays would result in preventable HPV-related cancer cases in future.Policy1-Cervix, an established modelling platform of dynamic HPV transmission, HPV natural history, cervical screening, treatment, and cancer survival that has been validated across several settings. The dynamic HPV transmission component of Policy1-Cervix incorporates HPV vaccination and was used to estimate HPV incidence by age under scenarios of disruption to vaccination coverage, compared to a no disruption scenario. The number of lifetime cervical cancer cases was subsequently estimated for the cohorts affected after explicitly modelling cervical screening (5-yearly HPV screening starting from age 25) (Policy1-Cervix model can be found at https://www.policy1.org/models/cervix/documentation.We used  age 25)  to take  age 25) . Data in age 25) . In a seA baseline scenario of uninterrupted HPV vaccination (status quo) assumed a two-dose uptake of HPV9 at age 12 of 82.4% among females and 75.5% among males. Three disruption scenarios were modelled affecting females and males born in 2008 cohort who were aged 12 in 2020 . Scenario 1 assumed a fast catch-up where vaccination was delayed by one year (but no doses were entirely missed); scenario 2 assumed a slow catch-up where vaccination was delayed between 1 and 7 years with an equal proportion being caught up each year; and scenario 3 assumed there was no catch-up, and therefore any protection in the cohort would be due to herd effects only. A fourth scenario was also conducted which assumed individuals born in 2008 and in 2009 , missed HPV vaccination at age 12, with no catch-up.For each scenario, we estimated the number of HPV-associated cancer cases (from age 12 to 84 years) prevented by vaccination compared to an unvaccinated comparator cohort, and the additional number of cases under each disruption scenario compared to the no disruption scenario. The study presents important findings for public health authorities and policymakers to enable them to make evidence-based decisions when deciding on how to manage the effect of HPV vaccination disruptions. This study is particularly relevant in light of the efforts of the WHO to achieve global elimination of cervical cancers. The findings are convincing and the model used is appropriate. public reviews designed to be posted alongside the preprint for the benefit of readers; (ii) feedback on the manuscript for the authors, including requests for revisions, shown below. We also include an acceptance summary that explains what the editors found interesting or important about the work.Our editorial process produces two outputs: (i) Decision letter after peer review:eLife. Your article has been reviewed by 2 peer reviewers, and the evaluation has been overseen by a Reviewing Editor and Diane Harper as the Senior Editor. The following individuals involved in the review of your submission have agreed to reveal their identity: Aura Timmen (Reviewer #1), Rebecca Luckett (Reviewer #2).Thank you for submitting your article "The impact of COVID-19-related disruptions to HPV vaccination – a modelled analysis" for consideration by The reviewers have discussed their reviews with one another, and the Reviewing Editor has drafted this to help you prepare a revised submission.Essential revisions:1. The abstract is difficult to follow. State more clearly what "natural history / vaccination / screening / HPV-related cancers" means in association with the model rather than putting it in parentheses. Similarly in the 3rd sentence, clarify what the "no disruption" scenario is as its own sentence, then explain what you are comparing it to. It may also help to have the 'n' of the background number of HPV-related cancers since n's are given later on for each scenario to give context to this finding. In the sentence starting with "additional". It is not clear what  and  mean after the two types of cancers from the abstract alone. These should either be explained or taken out. Finally, the difference between the fourth scenario and the "worst case scenario" is confusing.2. In the first introductory paragraph, please explain the content in parentheses to improve clarity.3. Methods: just as in the abstract, please clarify the fourth scenario and the difference in outcomes in the 2008 vs 2008-2009 affected cohorts.4. Results section: Given there are multiple scenarios given, in the opening Results section, please add "in the baseline scenario of no interruption of HPV vaccination…" or something similar to set the stage very clearly.5. There is space to expand on the results presented in Table 1, including an explanation of Affected cohorts 2008 vs Affected cohorts 2008-2009. It may also be useful to explain this analysis in the methods section.Reviewer #1 (Recommendations for the authors):Some considerations regarding how public debates about COVID-19 vaccination might have impacted the uptake of the HPV-vaccine might enrich the discussion.Reviewer #2 (Recommendations for the authors):– If 2020-2021 vaccination data is now available, could this be mentioned in the discussion .– The abstract is difficult to follow. State more clearly what "natural history / vaccination / screening / HPV-related cancers" means in association with the model rather than putting it in parentheses. Similarly in the 3rd sentence, clarify what the "no disruption" scenario is as its own sentence, then explain what you are comparing it to. It may also help to have the 'n' of the background number of HPV-related cancers since n's are given later on for each scenario to give context to this finding. In the sentence starting with "additional". It is not clear what  and  mean after the two types of cancers from the abstract alone. These should either be explained or taken out. Finally, the difference between the fourth scenario and the "worst case scenario" is confusing.– In the first introductory paragraph, I would recommend explaining the content in parentheses to improve clarity.– Methods: just the same comment as in the abstract to clarify the fourth scenario and the difference in outcomes in the 2008 vs 2008-2009 affected cohorts.– Results section: Given there are multiple scenarios given, in the opening Results section, I would suggest adding "in the baseline scenario of no interruption of HPV vaccination…" or something similar to set the stage very clearly.– There is space to expand on the results presented in Table 1, including an explanation of Affected cohorts 2008 vs Affected cohorts 2008-2009. It may also be useful to explain this analysis in the methods section.– Given that Australia is a best-case scenario and other countries have not had the same success in HPV vaccination coverage, in the discussion would it be possible to give a comparison of how these three scenarios would look different in a population with school-based vaccination but lower coverage volume such that readers could understand how much of the success / failures of each of the three catch-up scenarios? It would be particularly helpful for readers who are not familiar with the modeling tool used in this analysis. Essential revisions:1. The abstract is difficult to follow. State more clearly what "natural history / vaccination / screening / HPV-related cancers" means in association with the model rather than putting it in parentheses.We have removed the parenthesis and provided a clearer explanation of the model used. The relevant sentence has now been changed as shown below:“We used ‘Policy1-Cervix’, a dynamic model simulating HPV natural history, sexual behaviour, HPV transmission, vaccination, cervical screening, and diagnosis of HPV-related cancers, to estimate the impact on HPV-related cancers from disruptions to HPV vaccination in a high-income setting.”Similarly in the 3rd sentence, clarify what the "no disruption" scenario is as its own sentence, then explain what you are comparing it to.The ‘no disruption’ scenario has now been written in a single sentence as below:“A baseline scenario of no disruption to HPV vaccination was modelled, which assumed uptake of the nonavalent vaccine at age 12 by 82.4% among females and 75.5% among males, as is the coverage in Australia.”It may also help to have the 'n' of the background number of HPV-related cancers since n's are given later on for each scenario to give context to this finding.The background number of cases for the baseline ‘no disruption’ scenario has now been added as shown below:“Compared to 1,532 HPV-related cancer cases estimated for the baseline no disruption scenario, we found a 1-year delay could result in ≤0.3% more HPV-related cancers (n=4) but the increase would be greater if catch-up was slower , and especially if there was no catch-up .”In the sentence starting with "additional". It is not clear what  and  mean after the two types of cancers from the abstract alone. These should either be explained or taken out.The sentence has been amended as shown below for additional clarity:“Additional cancers for a single missed cohort were most commonly cervical (23%) and anal cancers (16%) in females and oropharyngeal cancers in males (20%).”Finally, the difference between the fourth scenario and the "worst case scenario" is confusing.We have amended the sentence describing the fourth scenario modelled as shown below, which was also the worst-case scenario, as individuals born in 2008 and in 2009 would not receive HPV vaccination.“A fourth scenario assumed no catch-up HPV vaccination for two birth cohorts, i.e. all individuals born in 2008 and in 2009 missed vaccination (worst case scenario).2. In the first introductory paragraph, please explain the content in parentheses to improve clarity.We have now amended the relevant sentence as indicated below:“Additionally, catch-up HPV vaccination was offered to females aged 14 to 26 years in 2007-2009 and to males aged 14-15 in 2013-2014.”3. Methods: just as in the abstract, please clarify the fourth scenario and the difference in outcomes in the 2008 vs 2008-2009 affected cohorts.We have amended the sentence explaining the fourth scenario more clearly, as shown below:“A fourth scenario was also conducted which assumed individuals born in 2008 and in 2009 , missed HPV vaccination at age 12, with no catch-up.”4. Results section: Given there are multiple scenarios given, in the opening Results section, please add "in the baseline scenario of no interruption of HPV vaccination…" or something similar to set the stage very clearly.We have amended the relevant sentence as indicated:“In the baseline scenario of no interruption to HPV vaccination, we estimate 2,583 HPV-related cancer cases would be prevented in the 2008 cohort due to HPV vaccination, equating to 63% of all HPV-related cases (Table 1).”5. There is space to expand on the results presented in Table 1, including an explanation of Affected cohorts 2008 vs Affected cohorts 2008-2009. It may also be useful to explain this analysis in the methods section.Table 1 has been updated to refer to “Outcomes in 2008 birth cohort” rather than “Affected cohort (2008)” and footnotes have been added to further clarify the affected cohorts.“* Includes outcomes specifically for the cohort consisting of females and males born in 2008 (any effects on the 2009 cohort are not included).** Includes outcomes specifically for the cohort consisting of females and males born in either 2008 or 2009.”In the methods section, reference had previously been included regarding the cohorts affected by the scenarios modelled. However, further clarification in wording has been provided as seen below:“Three disruption scenarios were modelled affecting females and males born in 2008 who were aged 12 in 2020 …. A fourth scenario was also conducted which assumed individuals born in 2008 and in 2009 , missed HPV vaccination at age 12, with no catch-up.”Reviewer #1 (Recommendations for the authors):Some considerations regarding how public debates about COVID-19 vaccination might have impacted the uptake of the HPV-vaccine might enrich the discussion.In the past, vaccine hesitancy impacted uptake of HPV vaccination in certain settings like Japan, Denmark and Ireland :e453-63). However, in Australia, coverage rates have been relatively high and improved since the National HPV Vaccination Program Register was established. In the Australian context, there isn’t strong evidence that the COVID-19 vaccine debate and hesitancy had any substantive impact on HPV vaccine uptake. We agree with the reviewer that a complex interaction between COVID-19 vaccine hesitancy and HPV vaccine hesitancy may have played out and impacted coverage in other settings. We have briefly referred to data from Europe indicating that there was a loss in confidence in the HPV vaccine between 2020 and 2022 in many countries.8 There are signs, however, of a decrease in vaccine confidence in Europe around the time of the COVID-19 pandemic, with lower confidence for the HPV vaccine reported in 17 countries in 2022 compared to 2020.”“Globally, the timeframe to reach elimination is likely to be impacted by pandemic-induced delays in HPV vaccination delivery and also by global shortages of the HPV vaccine estimated to last until 2024 thus delaying the introduction of vaccination in low- and middle-income countries.1415 In countries predicted to achieve cervical cancer elimination in the relatively short term, such as Australia, short delays of one year are not predicted to delay elimination.Reviewer #2 (Recommendations for the authors):– If 2020-2021 vaccination data is now available, could this be mentioned in the discussion .Final coverage data is reported as those who are vaccinated by age 15, and this is not yet available for the most affected cohorts . The latest coverage available is for those turning 15 in 2021, who were mostly offered vaccination at school in 2019 or earlier. To clarify this, we have updated the discussion as seen below:2 The difference in numbers suggest vaccination delays, possibly due to COVID-19 effects including school closures during lockdowns, and decreased school attendance due to infections. In line with WHO recommendations, final coverage data is reported as those who are vaccinated by age 15, and is not yet available for the most affected cohorts .10”“In Australia, initial national figures show for adolescents aged 11 to <15 years who received their first dose in 2020, 74.7% of girls and 72.6% of boys, received their second dose in the same calendar year compared to 86.2% and 84.3% for girls and boys, respectively, in 2019.– The abstract is difficult to follow. State more clearly what "natural history / vaccination / screening / HPV-related cancers" means in association with the model rather than putting it in parentheses.This has been addressed above , however, the response is also provided below for ease of access We have removed the parenthesis and provided a clearer explanation of the model used. The relevant sentence has now been changed to:“We used ‘Policy1-Cervix’, a dynamic model simulating HPV natural history, sexual behaviour, HPV transmission, vaccination, cervical screening, and diagnosis of HPV-related cancers, to estimate the impact on HPV-related cancers from disruptions to HPV vaccination in a high-income setting.”Similarly in the 3rd sentence, clarify what the "no disruption" scenario is as its own sentence, then explain what you are comparing it to.The ‘no disruption’ scenario has now been written in a single sentence as below:“A baseline scenario of no disruption to HPV vaccination was modelled, which assumed uptake of the nonavalent vaccine at age 12 by 82.4% among females and 75.5% among males, as is the coverage in Australia.”It may also help to have the 'n' of the background number of HPV-related cancers since n's are given later on for each scenario to give context to this finding.The background number of cases for the baseline ‘no disruption’ scenario has now been added as shown below:“Compared to 1,532 HPV-related cancer cases estimated for the baseline no disruption scenario, we found a 1-year delay could result in ≤0.3% more HPV-related cancers (n=4) but the increase would be greater if catch-up was slower , and especially if there was no catch-up .”In the sentence starting with "additional". It is not clear what  and  mean after the two types of cancers from the abstract alone. These should either be explained or taken out.The sentence has been amended as shown below in bold for additional clarity:“Additional cancers for a single missed cohort were most commonly cervical (23%) and anal cancers (16%) in females and oropharyngeal cancers in males (20%).”Finally, the difference between the fourth scenario and the "worst case scenario" is confusing.We have amended the sentence describing the fourth scenario modelled as shown below, which was also the worst-case scenario, as individuals born in 2008 and in 2009 would not receive HPV vaccination.“A fourth scenario assumed no catch-up HPV vaccination for two birth cohorts, i.e. all individuals born in 2008 and in 2009 missed vaccination (worst case scenario).”– In the first introductory paragraph, I would recommend explaining the content in parentheses to improve clarity.We have now amended the relevant sentence as indicated below:“Additionally, catch-up HPV vaccination was offered to females aged 14 to 26 years in 2007-2009 and to males aged 14-15 in 2013-2014.”– Methods: just the same comment as in the abstract to clarify the fourth scenario and the difference in outcomes in the 2008 vs 2008-2009 affected cohorts.We have amended the sentence explaining the fourth scenario more clearly, as shown below:“A fourth scenario was also conducted which assumed individuals born in 2008 and in 2009 , missed HPV vaccination at age 12, with no catch-up.”– Results section: Given there are multiple scenarios given, in the opening Results section, I would suggest adding "in the baseline scenario of no interruption of HPV vaccination…" or something similar to set the stage very clearly.We have amended the relevant sentence as indicated:“In the baseline scenario of no interruption to HPV vaccination, we estimate 2,583 HPV-related cancer cases would be prevented in the 2008 cohort due to HPV vaccination, equating to 63% of all HPV-related cases (Table 1).”– There is space to expand on the results presented in Table 1, including an explanation of Affected cohorts 2008 vs Affected cohorts 2008-2009. It may also be useful to explain this analysis in the methods section.Please refer to response provided to editor on the same question (comment 5).– Given that Australia is a best-case scenario and other countries have not had the same success in HPV vaccination coverage, in the discussion would it be possible to give a comparison of how these three scenarios would look different in a population with school-based vaccination but lower coverage volume such that readers could understand how much of the success / failures of each of the three catch-up scenarios? It would be particularly helpful for readers who are not familiar with the modeling tool used in this analysis.We have added some commentary in the discussion in response to the reviewer’s comment. In future, further similar work in countries with lower base coverage would be informative.“Australia is a relatively high HPV vaccination coverage setting. Outcomes may be less favourable in a lower coverage setting, as there would be less protection from herd effects; however, the impact of disruptions might also be smaller in a setting with lower coverage, since a lower coverage program would be less effective. Nevertheless, the finding that if catch-up is performed expeditiously then it mitigates much of the effect from vaccination delays, is likely to hold in other settings. In a previous study : e223-e234) modelling the health impacts of HPV vaccination hesitancy in Japan from 2013 to 2019 and the potential effects of restoring coverage to 70% with catch-up vaccination in 2020 is informative as it demonstrates that multi-age HPV catch-up vaccination, after catastrophic falls in coverage in Japan, would be effective in mitigating the effects.”


Classical and optimal control architectures for motion mechanics in the presence of noisy sensors use different algorithms and calculations to perform and control any number of physical demands, to varying degrees of accuracy and precision in regards to the system meeting the desired end state. To circumvent the deleterious effects of noisy sensors, a variety of control architectures are suggested, and their performances are tested for the purpose of comparison through the means of a Monte Carlo simulation that simulates how different parameters might vary under noise, representing real-world imperfect sensors. We find that improvements in one figure of merit often come at a cost in the performance in the others, especially depending on the presence of noise in the system sensors. If sensor noise is negligible, open-loop optimal control performs the best. However, in the overpowering presence of sensor noise, using a control law inversion patching filter performs as the best replacement, but has significant computational strain. The control law inversion filter produces state mean accuracy matching mathematically optimal results while reducing deviation by 36%. Meanwhile, rate sensor issues were more strongly ameliorated with 500% improved mean and 30% improved deviation. Inverting the patching filter is innovative but consequently understudied and lacks well-known equations to use for tuning gains. Therefore, such a patching filter has the additional drawback of having to be tuned through trial and error. Artemis I will be the first integrated flight test of NASA’s deep space exploration system: the Orion spacecraft, Space Launch System (SLS) rocket, and the ground systems at Kennedy Space Center in Cape Canaveral, Florida. The first in a series of increasingly complex missions, Artemis I  will be Dealing with the fusion of potentially poor, noisy sensors is a ubiquitous challenge that has a long lineage leading to several disparate approaches. Some researchers focus on improving the sensor itself or its signal using internal algorithms. Others seek to develop architectures that prove robust to fused noisy sensor data. Wang et al. proposed a novel method for accurate, autonomous and real-time orbit determinations for geo-referencing with a standalone global positioning system receiver . Xiong eLeake et al. proposed dealing with sensor issues with improved sensor algorithms, proposing a non-dimensional star identification algorithm compared in terms of accuracy, speed, and robustness to the so-called pyramid algorithm . Marin eRather than dealing with sensor issue algorithmically as proposed by Opromolla, Chen et al. instead focused on the control algorithm using the sensor measurements and proposed a velocity-based impedance control scheme illustrating efficacy in both speed and robustness . This maControllers are differential equations that are designed to be able to manipulate some state variable by arbitrarily changing a variable connected to it through a physical law or equation. They often feature several points of adjustment and tunability to fit figures of merit desired by the designer. The figures of merit utilized here include spacecraft tracking accuracy (how well the controller reaches the desired target), precision (as measured by deviation), and cost . Computational burden is also monitored since difficulties such as singular matrix inversions are involved. A variety of control system architectures were evaluated, and their ability is assessed to perform the task of a rest-to-rest reorientation normalized to unity. The different architecture’s performance under the previously mentioned figures of merit will be compared to show how they respond to a same noise environment, and which one best mitigates the effects of noisy sensors.Open-loop optimal results are analytically calculated providing a performance benchmark for comparing other methods.Inspired by Opromolla, 2015 , velocitReal-time optimal control is compared since it was the latest cited proposals of 2022, and can be considered state of the art for this application, as an analytic optimal solution is found, which is not always possible for a generic system.Double-integrator patching filters are implemented seeking to match open-loop optimal results amidst the fusion of noisy sensors.System-inverting patching filters are implemented, also seeking to match open-loop optimal results amidst the fusion of noisy sensors.This paper will focus on changes to the control architecture .The controllers will perform a rest-to-rest reorientation of one unit of rotation (indicated by variable not the rate error (see (14)). P+V controllers can be easily tuned to fit desired settling times and damping ratios. For a maximum tolerance of 2% error at the desired settling time, Equation (7):The P+V controller is a form of classical control, tuned using two different gains: a proportional gain P+V controllers are always able to reach the desired value, but it is the selection of gains that affects how quickly it is reached. This ability is hampered by noise, especially on the rate sensor. Because the end rate is 0, any error in rate detection will cause a control to move the system off of the desired value. Additionally, the settling time is only for the state target, so no estimation of the rate target settling time is used to set the gains.the task at hand  is found:Real-time optimal control, or RTOC, is a modification of the previous iteration of optimal control that considers the current state of the system, allowing the controller to adjust for noise and perturbations. The top two rows of the matrix in (11) are the equations for The vector of unknowns on the left-hand side is calculated by inverting the matrix and multiplying it by the vector of knowns on the right-hand side. The unknowns While being able to change course based on the current state of the system is an advantage over open-loop optimal control, RTOC has a large computational demand in its inversion of a 4 × 4 matrix. Additionally, the matrix becomes singular as One way to combine the analytical accuracy of optimal control and the computational simplicity and tunability of classical P+V control is to impose a ‘patching’ filter that integrates the optimal control However, the result of the previous architecture may not be desirable. Should the gains of the original P+V controller be modifiable, tuning them around the patching filter is a viable strategy. This architecture is not as well studied as the original P+V control, so handy equations based around desired settling time and damping ratio are not available. Therefore, the gains will be tuned by hand, i.e., trial and error, until the result meets acceptable figures of merit.Should the gains not be modifiable, there is another way to adjust the architecture. Instead of directly integrating the optimal control, the control law for the P+V controller can be solved for an optimal input such that, after all the gains are applied and the control calculated, the P+V controller output matches that of the optimal control Entering the optimal values Equation (17) is the patching filter to be applied to the optimal control yielding the optimal state trajectory input for the P+V controller.The following simulations were performed in MATLAB Simulink, using the ode4 (Runge—Kutta) integrator and a 0.01s step size. Using a random number generator with a Gaussian distribution, a noise signal was added to the state and rate with variances of 0.0001 with zero mean. The moment of inertia was also varied randomly but uniformly to Displayed in J) can be evaluated. The P+V controller, while having the smallest standard deviations for both values, has notable error in From The double-integrator patching filter has the second-lowest spreads in both state and rate and the lowest cost, but the final values are completely off the mark; 16% error in state and 943% more rate error than the next highest architecture. After some tuning, it performs similarly to the P+V controller but with higher spreads , lower cost (−66.8%), and a more accurate final rate (12% the error of the P+V). Finally, the control law inversion patching filter strikes a balance between all figures of merit: lowest state error, third lowest state spread, second lowest rate error, third lowest state spread, and a cost only marginally higher (0.7%) than the optimal From the results shown in The controller achieved the best angle tracking deviation, but the worst cost performance.Velocity-based classical control was investigated in the prequels and established as the comparative benchmark here where open-loop optimal results in item #2 were used for initial comparison. Open-loop optimal results were presented analytically providing a performance benchmark for comparing other proposed methods.Real-time optimal control was presented and compared to the benchmarks.These filters achieved the best velocity tracking performance.Double-integrator patching filters were introduced seeking to match open-loop optimal results amidst fusion of noisy sensors. System-inverting patching filters were implemented also seeking to match open-loop optimal results amidst fusion of noisy sensors. These patching filters achieved the best overall performance with notable improvements amidst no dramatic performance degradation in any categories of performance.The P+V controller has high cost and rate error, the optimal controls have low cost and high accuracy but higher susceptibility to sensor noise, while the double-integrator patching filter is difficult to tune and costly. The control law inversion patching filter, however, can be seen as the best alternative to open-loop optimal control, especially in the presence of sensor noise and inertia uncertainties, as it had a cost only slightly higher (0.7%) with smaller standard deviations  and final results more accurate than any other architecture . The key tradeoff was computational burden since control inversion optimization took 25–40% longer to run than some of the other architectures.Recommendation: In instances where performance must be induced on pre-existing systems, control inversion patching filters are advised. □


The HPV Serology Laboratory is leading a global partnership initiative aiming for standardization and harmonization of current serology assay platforms being used to assess immune responses to HPV vaccines. Serology standardization is particularly important given the increasing number of immunobridging trials relying on serology data for approval of new vaccine dosing schedules or vaccine formulations. The initiative was established in 2017 to enable comparisons of data between different vaccines and relevant studies as well as expedite the implementation of new vaccines and vaccine indications. The HPV Serology Laboratory has held or attended several meetings with partnering laboratories, including international meetings in 2017, 2018, and 2021. To date, the licensed human papillomavirus (HPV) prophylactic vaccines have demonstrated robust immunogenicity and efficacy –4. AlthoBuilding on serology assay standardization and harmonization efforts initiated by the World Health Organization (WHO), HPV LabNet in 2006, a joint meeting with several institutions, organized by Ligia Pinto from Frederick National Laboratory for Cancer Research (FNLCR) and Elizabeth Unger from Centers for Disease Control and Prevention (CDC), was held in March 2016 to collectively recognize the growing need for standardization and harmonization. The participants of the meeting included the Bill & Melinda Gates Foundation, NCI, CDC, United States Food and Drug Administration (FDA), WHO, GlaxoSmithKline (GSK), Merck, Innovax, National Institute for Biological Standards and Control (NIBSC), Public Health England, and several US and international universities and research institutes.Briefly, in response to the initial convention, the HPV Serology Laboratory (HPVSL) at FNLCR was established in January 2017 to address this challenge, in partnership with the National Cancer Institute and the Bill & Melinda Gates Foundation. A follow up meeting at the 32nd International Papillomavirus Conference in Sydney, Australia from October 2 to 6, 2018, was convened to discuss the progress of main aims, challenges, and some of the future needs. The outcomes of this meeting included definition of the primary mission of the initiative, which was to enable comparisons of data between different vaccines and different relevant studies, as well as expedite the implementation of new vaccines and vaccine indications. The specific aims to drive these goals include:The development of a qualified secondary assay standard and a bank of serum specimens to use as assay proficiency panels for 9 HPV types (HPV-6/11/16/18/31/33/45/52/58) included in the licensed HPV vaccines.The production of qualified reference reagents (HPV Virus-Like Particles) by establishing a set of criteria or guidelines for qualification.The development of a validated multiplex serology assay to enable immunogenicity monitoring in HPV vaccine trials.The promotion of the use of standards through platforms such as meetings, publications, data, and protocol sharing.We herein briefly describe the progress to each of the 4 objectives as well as provide the links to all currently developed standard operating procedures (SOPs).First, HPVSL was able to generate qualified secondary standards calibrated against HPV-16 and HPV-18 WHO International Standards (IS). For this effort, 144 human serum samples were obtained from various sample providers, and each sample was screened and categorized depending on the specific antibody response for each HPV type. Moreover, an HPV assay proficiency panel of 80 samples covering a wide range of HPV antibody responses was established. Currently, the proficiency panel has been distributed and tested by 10 laboratories with their respective antibody binding or pseudovirion-based neutralization assays.Second, the production of the first lot of qualified VLPs for multiple HPV types (HPV-6/11/16/18/31/33/45/52/58) was completed at the time of the follow up meeting in 2018. These reagents will be available for reference use in assays in respective laboratories.Third, a high-throughput Luminex bead-based 9-plex immunoassay was developed and a validation plan for the HPV-16 and HPV-18 ELISAs and multiplex assay was drafted. To date, the 9-plex assay validation has been completed and guidance documents for data processing and analyses are under development.Lastly, efforts have been made to promote the development and use of standards, SOPs, and data . Up to 8https://www.nibsc.org/products/brm_product_catalogue/sub_category_listing.aspx?category=Vaccines&subcategory=Human%20Papillomavirus).As part of this initiative, the HPVSL has been collaborating with NIBSC and WHO to develop International Standards for the remaining HPV types in the nonavalent vaccine, including HPV high-risk types  and low-risk types (HPV-6 and HPV-11). These standards were recently approved by WHO and are now available for request through NIBSC’s website (Future directions discussed by the initiative consisted of (1) implementation of high-throughput HPV antibody testing using Good Clinical Laboratory Practices (GCLP) to support ongoing and future vaccine immunogenicity trials; and (2) development of an HPV Vaccine Trial Network of laboratories involved in the testing of HPV vaccines to expand training capability as well as establish an Assay Proficiency Panel Program.In June 2021, a virtual meeting was held on June 29 to 30, 2021, to review progress of the standardization initiative thus far and to bridge scientific gaps and outstanding questions. The main aims and outcomes of the meeting were to discuss: (1) standardization of assays and reagents; (2) International Standard Calibration procedures; (3) assay cut-off values; (4) current immunobridging clinical trials; (5) gaps and challenges in standardization of HPV serology. A total of 119 scientists and clinicians from 13 countries, representing 36 institutions and industries, participated in the meeting to update the community on the progress on the objectives of the initiative. Participants also reported on advancements made by the HPV serology community in exploring and advancing with new vaccine dosing schedules or vaccine formulations. A report summarizing the meeting has been recently published [