Seroepidemiological assessment of the spread of SARS-CoV-2 among 25 and 28 year-old adult women in Finland between March 2020-June 2022.

INTRODUCTION: Serological surveys of the prevalence of SARS-CoV-2 are instrumental to understanding the course of the COVID-19 epidemic. We evaluate the seroprevalence of SARS-CoV-2 among young adult Finnish females residing in 25 communities all over Finland from 2020 until 2022. METHODS: Between 1st March 2020 and 30th June 2022, 3589 blood samples were collected from 3583 women born in 1992-95 when aged 25 or 28 years old attending the follow-up of an ongoing population-based trial of cervical screening strategies. The crude and population standardized SARS-CoV-2 seroprevalence was measured using nucleocapsid (induced by infection) and spike wild-type (WT) protein (induced both by infection and by vaccination) antigens over time and stratified by place of residence (inside or outside the Helsinki metropolitan region). RESULTS: During 2020 (before vaccinations), spike-WT and nucleocapsid IgG antibodies followed each other closely, at very low levels (<5%). Spike-WT seropositivity increased rapidly concomitant with mass vaccinations in 2021 and reached 96.3% in the 2nd quartile of 2022. Antibodies to nucleocapsid IgG remained relatively infrequent throughput 2020-2021, increasing rapidly in the 1st and 2nd quartiles of 2022 (to 19.7% and 56.6% respectively). The nucleocapsid IgG seropositivity increased more profoundly in participants residing in the Helsinki metropolitan region (4.5%, 8.4% and 43.9% in 2020, 2021 and 2022 respectively) compared to those residing in communities outside the capital region (4.5%, 4.3% and 34.7%). CONCLUSIONS: Low SARS-CoV-2 infection-related seroprevalence during 2020-2021 suggest a comparatively successful infection control. Antibodies to the SARS-CoV-2 WT spike protein became extremely common among young women by the end of 2021, in line with the high uptake of SARS-CoV-2 vaccination. Finally, the rapid increase of seroprevalences to the SARS-CoV-2 nucleocapsid protein during the first and second quartile of 2022, imply a high incidence of infections with SARS-CoV-2 variants able to escape vaccine-induced protection.

Low methylation marker levels among human papillomavirus-vaccinated women with cervical high-grade squamous intraepithelial lesions.

Cervical cancer screening programs, including triage tests, need redesigning as human papillomavirus (HPV)-vaccinated women are entering the programs. Methylation markers offer a potential solution to reduce false-positive rates by identifying clinically relevant cervical lesions with progressive potential. In a nested case-control study, 9242 women who received the three-dose HPV16/18-vaccine at ages 12-15 or 18 in a community-randomized trial were included. Subsequently, they were re-randomized for either frequent or infrequent cervical cancer screening trials. Over a 15-year post-vaccination follow-up until 2022, 17 high-grade squamous intraepithelial lesion (HSIL) and 15 low-grade (LSIL) cases were identified at the 25-year screening round, alongside 371 age and community-matched HPV16/18-vaccinated controls. Methylation analyses were performed on cervical samples collected at age 25, preceding histologically confirmed LSIL or HSIL diagnoses. DNA methylation of viral (HPV16/18/31/33) and host-cell genes (EPB41L3, FAM19A4, and miR124-2) was measured, along with HPV-genotyping. No HPV16/18 HSIL cases were observed. The predominant HPV-genotypes were HPV52 (29.4%), HPV59/HPV51/HPV58 (each 23.5%), and HPV33 (17.7%). Methylation levels were generally low, with no significant differences in mean methylation levels of viral or host-cell genes between the LSIL/HSIL and controls. However, a significant difference in methylation levels was found between HSIL cases and controls when considering a combination of viral genes and EPB41L3 (p value = .0001). HPV-vaccinated women with HSIL had HPV infections with uncommon HPV types that very rarely cause cancer and displayed low methylation levels. Further investigation is warranted to understand the likely regressive nature of HSIL among HPV-vaccinated women and its implications for management.

Exploring the Associations of Inflammatory and Oxidative Stress Biomarkers with Pancreatic Diseases: An Observational and Mendelian Randomisation Study.

Identifying biomarkers linked to pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP) is crucial for early detection, treatment, and prevention. Methods: Association analyses of 10 serological biomarkers involved in cell signalling (IFN-γ, IL-6, IL-8, IL-10), oxidative stress (superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzyme activities, total glutathione (GSH), malondialdehyde (MDA) levels), and intestinal permeability proteins (zonulin, I-FABP2) were conducted across PDAC (n = 12), CP (n = 21) and control subjects (n = 23). A Mendelian randomisation (MR) approach was used to assess causality of the identified significant associations in two large genetic cohorts (FinnGen and UK Biobank). Results: Observational results showed a downregulation of SOD and GPx antioxidant enzyme activities in PDAC and CP patients, respectively, and higher MDA levels in CP patients. Logistic regression models revealed significant associations between CP and SOD activity (OR = 0.21, 95% CI [0.05, 0.89], per SD), GPx activity (OR = 0.28, 95% CI [0.10, 0.79], per SD), and MDA levels (OR = 2.05, 95% CI [1.36, 3.08], per SD). MR analyses, however, did not support causality. Conclusions: These findings would not support oxidative stress-related biomarkers as potential targets for pancreatic diseases prevention. Yet, further research is encouraged to assess their viability as non-invasive tools for early diagnosis, particularly in pre-diagnostic CP populations.

Ecological diversity profiles of non-vaccine-targeted HPVs after gender-based community vaccination efforts.

The long-term effect of population-level human papillomavirus (HPV) vaccination on the viral ecology of the untargeted HPVs is poorly understood. We performed an 8-year follow-up of 33 communities randomized to gender-neutral HPV16/18 vaccination, girls-only HPV16/18 vaccination, and control communities without HPV vaccination. The 1992/93 and 1994 birth cohorts were invited in school years 2007/8 and 2008/9. Follow-up cervico-vaginal sampling at 18 and 22 years of age, 4 and 8 years post-vaccination, respectively, were attended by 11,396 and 5,602 participants. HPV types 6/11/16/18/31/33/35/39/45/51/52/56/58/59/66/68 were genotyped and used for the community-level ecological diversity estimations. Gender-neutral vaccination communities with a stronger herd immunity than girls-only vaccination communities show a significantly increased HPV α-diversity (p = 1.1 × 10-8) from 4 to 8 years post-vaccination, despite the clearance of the vaccine-targeted HPVs in these communities. This likely sign of niche occupation by the non-vaccine-targeted HPVs will potentially affect the future cervical cancer screening programs but should not interfere with the WHO mission to eliminate cervical cancer.

Biophysical Properties of Bifunctional Phage-Biosensor.

Biosensor research is a swiftly growing field for developing rapid and precise analytical devices for biomedical, pharmaceutical, and industrial use and beyond. Herein, we propose a phage-based biosensor method to develop a sensitive and specific system for biomedical detection. Our method is based on in vitro selected phages and their interaction with the targeted analytes as well as on optical properties that change according to the concentration of the model analyte. The green fluorescent protein (GFP) was chosen as our model analyte as it has its own well-known optical properties. Brilliant green was used as a reporter component for the sensor. Its presence enables a color intensity (absorbance) change when the analyte is present in the solution. Furthermore, the reporter dye functioned as a quencher for an additional lanthanide label in our assay. It mediated the specific phage-derived interference in the signal measured with the time-resolved luminescence. Most importantly, our results confirmed that the presented bifunctional phage with its liquid crystal properties enabled the measurement of GFP in a concentration-dependent, quantitative manner with a limit of detection of 0.24 µg/mL. In the future, our novel method to develop phage-based biosensors may provide highly sensitive and specific biosensors for biomedical or otherwise-relevant targets.

Assessing the risk of cervical neoplasia in the post-HPV vaccination era.

This review is based on the recent EUROGIN scientific session: "Assessing risk of cervical cancer in the post-vaccination era," which addressed the demands of cervical intraepithelial neoplasia (CIN)/squamous intraepithelial lesion (SIL) triage now that the prevalence of vaccine-targeted oncogenic high-risk (hr) human papillomaviruses (HPVs) is decreasing. Change in the prevalence distribution of oncogenic HPV types that follows national HPV vaccination programs is setting the stage for loss of positive predictive value of conventional but possibly also new triage modalities. Understanding the contribution of the latter, most notably hypermethylation of cellular and viral genes in a new setting where most oncogenic HPV types are no longer present, requires studies on their performance in vaccinated women with CIN/SIL that are associated with nonvaccine HPV types. Lessons learned from this research may highlight the potential of cervical cells for risk prediction of all women's cancers.

Drug-induced tumor-specific cytotoxicity in a whole tissue ex vivo model of human pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer. PDAC has a dismal prognosis and an inherent resistance to cytostatic drugs. The lack of reliable experimental models is a severe limitation for drug development targeting PDAC. We have employed a whole tissue ex vivo culture model to explore the effect of redox-modulation by sodium selenite on the viability and growth of PDAC. Drug-resistant tumors are more vulnerable to redox-active selenium compounds because of high metabolic activity and redox imbalance. Sodium selenite efficiently and specifically reduced PDAC cell viability (p <0.02) (n=8) and decreased viable de novo tumor cell outgrowth (p<0.05) while preserving non-neoplastic tissues. Major cellular responses (damaged tumor cells > 90%, tumor regression grades III-IV according to Evans) were observed for sodium selenite concentrations between 15-30 µM. Moreover, selenium levels used in this study were significantly below the previously reported maximum tolerated dose for humans. Transcriptome data analysis revealed decreased expression of genes known to drive PDAC growth and metastatic potential (CEMIP, DDR2, PLOD2, P4HA1) while the cell death-inducing genes (ATF3, ACHE) were significantly upregulated (p<0.0001). In conclusion, we report that sodium selenite has an extraordinary efficacy and specificity against drug-resistant pancreatic cancer in an organotypic slice culture model. Our ex vivo organotypic tissue slice culture model can be used to test a variety of drug candidates for swift and reliable drug responses to individual PDAC cases.

Meta-Analysis and Validation of a Colorectal Cancer Risk Prediction Model Using Deep Sequenced Fecal Metagenomes.

The gut microbiome is a potential modifiable risk factor for colorectal cancer (CRC). We re-analyzed all eight previously published stool sequencing data and conducted an MWAS meta-analysis. We used cross-validated LASSO predictive models to identify a microbiome signature for predicting the risk of CRC and precancerous lesions. These models were validated in a new study, Colorectal Cancer Screening (COLSCREEN), including 156 participants that were recruited in a CRC screening context. The MWAS meta-analysis identified 95 bacterial species that were statistically significantly associated with CRC (FDR < 0.05). The LASSO CRC predictive model obtained an area under the receiver operating characteristic curve (aROC) of 0.81 (95%CI: 0.78−0.83) and the validation in the COLSCREEN dataset was 0.75 (95%CI: 0.66−0.84). This model selected a total of 32 species. The aROC of this CRC-trained model to predict precancerous lesions was 0.52 (95%CI: 0.41−0.63). We have identified a signature of 32 bacterial species that have a good predictive accuracy to identify CRC but not precancerous lesions, suggesting that the identified microbes that were enriched or depleted in CRC are merely a consequence of the tumor. Further studies should focus on CRC as well as precancerous lesions with the intent to implement a microbiome signature in CRC screening programs.

Head-to-Head Comparison of Bi- and Nonavalent Human Papillomavirus Vaccine-Induced Antibody Responses.

For head-to-head comparison of human papillomavirus (HPV) antibody levels induced by different vaccines, 25-year-old vaccine-naive women were given either the bivalent (n = 188) or the nonavalent HPV vaccine (n = 184). Six months after vaccination antibodies against pseudovirions from 17 different HPV types (HPV6/11/16/18/31/33/35/39/45/51/52/56/58/59/66/68/73) were measured. Antibodies against HPV16/18 were higher after bivalent HPV vaccination (mean international units [IU] 1140.1 and 170.5 for HPV16 and 18, respectively) than after nonavalent vaccination (265.1 and 22.3 IUs, respectively). The bivalent vaccine commonly induced antibodies against the nonvaccine HPV types 31/33/35/45 or 58. The nonavalent vaccine induced higher antibodies against HPV6/11/31/33/45/52/58 and 35.

Human exposome assessment platform.

The Human Exposome Assessment Platform (HEAP) is a research resource for the integrated and efficient management and analysis of human exposome data. The project will provide the complete workflow for obtaining exposome actionable knowledge from population-based cohorts. HEAP is a state-of-the-science service composed of computational resources from partner institutions, accessed through a software framework that provides the world's fastest Hadoop platform for data warehousing and applied artificial intelligence (AI). The software, will provide a decision support system for researchers and policymakers. All the data managed and processed by HEAP, together with the analysis pipelines, will be available for future research. In addition, the platform enables adding new data and analysis pipelines. HEAP's final product can be deployed in multiple instances to create a network of shareable and reusable knowledge on the impact of exposures on public health.

Potential SARS-CoV-2 infectiousness among asymptomatic healthcare workers.

A majority of SARS-CoV-2 infections are transmitted from a minority of infected subjects, some of which may be symptomatic or pre-symptomatic. We aimed to quantify potential infectiousness among asymptomatic healthcare workers (HCWs) in relation to prior or later symptomatic disease. We previously (at the onset of the SARS-CoV-2 epidemic) performed a cohort study of SARS-CoV-2 infections among 27,000 healthcare workers (HCWs) at work in the capital region of Sweden. We performed both SARS-CoV-2 RT-PCR and serology. Furthermore, the cohort was comprehensively followed for sick leave, both before and after sampling. In the present report, we used the cohort database to quantify potential infectiousness among HCWs at work. Those who had sick leave either before or after sampling were classified as post-symptomatic or pre-symptomatic, whereas the virus-positive subjects with no sick leave were considered asymptomatic. About 0.2% (19/9449) of HCW at work were potentially infectious and pre-symptomatic (later had disease) and 0.17% (16/9449) were potentially infectious and asymptomatic (never had sick leave either before nor after sampling). Thus, 33% and 28% of all the 57 potentially infectious subjects were pre-symptomatic or asymptomatic, respectively. When a questionnaire was administered to HCWs with past infection, only 10,5% of HCWs had had no indication at all of having had SARS-CoV-2 infection ("truly asymptomatic"). Our findings provide a unique quantification of the different groups of asymptomatic, potentially infectious HCWs.

Risk for SARS-CoV-2 infection in healthcare workers outside hospitals: A real-life immuno-virological study during the first wave of the COVID-19 epidemic.

OBJECTIVES: Most COVID-19 related infections and deaths may occur in healthcare outside hospitals. Here we explored SARS-CoV-2 infections among healthcare workers (HCWs) in this setting. DESIGN: All healthcare providers in Stockholm, Sweden were asked to recruit HCWs at work for a study of past or present SARS-CoV-2 infections among HCWs. Study participants This study reports the results from 839 HCWs, mostly employees of primary care centers, sampled in June 2020. RESULTS: SARS-CoV-2 seropositivity was found among 12% (100/839) of HCWs, ranging from 0% to 29% between care units. Seropositivity decreased by age and was highest among HCWs <40 years of age. Within this age group there was 19% (23/120) seropositivity among women and 11% (15/138) among men (p<0.02). Current infection, as measured using PCR, was found in only 1% and the typical testing pattern of pre-symptomatic potential "superspreaders" found in only 2/839 subjects. CONCLUSIONS: Previous SARS-CoV-2 infections were common among younger HCWs in this setting. Pre-symptomatic infection was uncommon, in line with the strong variability in SARS-CoV-2 exposure between units. Prioritizing infection prevention and control including sufficient and adequate personal protective equipment, and vaccination for all HCWs are important to prevent nosocomial infections and infections as occupational injuries during an ongoing pandemic.

How infectious diseases arrived in the colonial Americas.

Analysis of viral DNA from human remains suggests that the transatlantic slave trade may have introduced new pathogens that contributed to the devastating disease outbreaks in colonial Mexico.

Differences in risk for SARS-CoV-2 infection among healthcare workers.

Healthcare workers (HCWs) are a risk group for SARS-CoV-2 infection, but which healthcare work that conveys risk and to what extent such risk can be prevented is not clear. Starting on April 24th, 2020, all employees at work (n = 15,300) at the Karolinska University Hospital, Stockholm, Sweden were invited and 92% consented to participate in a SARS-CoV-2 cohort study. Complete SARS-CoV-2 serology was available for n = 12,928 employees and seroprevalences were analyzed by age, sex, profession, patient contact, and hospital department. Relative risks were estimated to examine the association between type of hospital department as a proxy for different working environment exposure and risk for seropositivity, adjusting for age, sex, sampling week, and profession. Wards that were primarily responsible for COVID-19 patients were at increased risk (adjusted OR 1.95 (95% CI 1.65-2.32) with the notable exception of the infectious diseases and intensive care units (adjusted OR 0.86 (95% CI 0.66-1.13)), that were not at increased risk despite being highly exposed. Several units with similar types of work varied greatly in seroprevalences. Among the professions examined, nurse assistants had the highest risk (adjusted OR 1.62 (95% CI 1.38-1.90)). Although healthcare workers, in particular nurse assistants, who attend to COVID-19 patients are a risk group for SARS-CoV-2 infection, several units caring for COVID-19 patients had no excess risk. Large variations in seroprevalences among similar units suggest that healthcare work-related risk of SARS-CoV-2 infection may be preventable.

Severe features during outbreak but low mortality observed immediately before and after a March-May 2020 COVID-19 outbreak in Stockholm, Sweden.

OBJECTIVES: The aim of this study was to estimate how well the excess mortality reflected the burden of coronavirus disease 2019 (COVID-19)-related deaths during the March-May 2020 COVID-19 outbreak in Stockholm, Sweden, and whether the excess mortality during the outbreak might have resulted in a compensatory reduced mortality after the outbreak. METHODS: Using previous 10-year or 5-year average mortality rates as a baseline, the excess mortality estimates before, during, and after the COVID-19 outbreak in March-May 2020 in Stockholm were compared. RESULTS: Weekly death estimates revealed that the immediate pre-outbreak and post-outbreak all-cause mortality did not exceed to excess mortality regardless of whether previous 10-year or 5-year average mortality was used. Forty-three days after the start of the outbreak, 74.4% of the total excess mortality was reportedly explained by known COVID-19-related deaths, and the present study reports an update, showing that 15 weeks after the start of the outbreak, the reported COVID-19-related deaths explained >99% of the total excess mortality. CONCLUSIONS: An exceptional outbreak feature of rapid excess mortality was observed. However, no excess but similarly low mortality was observed immediately prior to the outbreak and post-outbreak, thus emphasizing the severity of the first wave of the COVID-19 outbreak in Stockholm.

Human papillomavirus seroprevalence in pregnant women following gender-neutral and girls-only vaccination programs in Finland: A cross-sectional cohort analysis following a cluster randomized trial.

BACKGROUND: Cervical cancer elimination through human papillomavirus (HPV) vaccination programs requires the attainment of herd effect. Due to its uniquely high basic reproduction number, the vaccination coverage required to achieve herd effect against HPV type 16 exceeds what is attainable in most populations. We have compared how gender-neutral and girls-only vaccination strategies create herd effect against HPV16 under moderate vaccination coverage achieved in a population-based, community-randomized trial. METHODS AND FINDINGS: In 2007-2010, the 1992-1995 birth cohorts of 33 Finnish communities were randomized to receive gender-neutral HPV vaccination (Arm A), girls-only HPV vaccination (Arm B), or no HPV vaccination (Arm C) (11 communities per trial arm). HPV16/18/31/33/35/45 seroprevalence differences between the pre-vaccination era (2005-2010) and post-vaccination era (2011-2016) were compared between all 8,022 unvaccinated women <23 years old and resident in the 33 communities during 2005-2016 (2,657, 2,691, and 2,674 in Arms A, B, and C, respectively). Post- versus pre-vaccination-era HPV seroprevalence ratios (PRs) were compared by arm. Possible outcome misclassification was quantified via probabilistic bias analysis. An HPV16 and HPV18 seroprevalence reduction was observed post-vaccination in the gender-neutral vaccination arm in the entire study population (PR16 = 0.64, 95% CI 0.10-0.85; PR18 = 0.72, 95% CI 0.22-0.96) and for HPV16 also in the herpes simplex virus type 2 seropositive core group (PR16 = 0.64, 95% CI 0.50-0.81). Observed reductions in HPV31/33/35/45 seroprevalence (PR31/33/35/45 = 0.88, 95% CI 0.81-0.97) were replicated in Arm C (PR31/33/35/45 = 0.79, 95% CI 0.69-0.90). CONCLUSIONS: In this study we only observed herd effect against HPV16/18 after gender-neutral vaccination with moderate vaccination coverage. With only moderate vaccination coverage, a gender-neutral vaccination strategy can facilitate the control of even HPV16. Our findings may have limited transportability to other vaccination coverage levels. TRIAL REGISTRATION: ClinicalTrials.gov number NCT00534638, https://clinicaltrials.gov/ct2/show/NCT00534638.

High Amounts of SARS-CoV-2 Precede Sickness Among Asymptomatic Health Care Workers.

BACKGROUND: Whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity among asymptomatic subjects reflects past or future disease may be difficult to ascertain. METHODS: We tested 9449 employees at Karolinska University Hospital, Stockholm, Sweden for SARS-CoV-2 RNA and antibodies, linked the results to sick leave records, and determined associations with past or future sick leave using multinomial logistic regression. RESULTS: Subjects with high amounts of SARS-CoV-2 virus, indicated by polymerase chain reaction (PCR) cycle threshold (Ct) value, had the highest risk for sick leave in the 2 weeks after testing (odds ratio [OR], 11.97; 95% confidence interval [CI], 6.29-22.80) whereas subjects with low amounts of virus had the highest risk for sick leave in the 3 weeks before testing (OR, 6.31; 95% CI, 4.38-9.08). Only 2.5% of employees were SARS-CoV-2 positive while 10.5% were positive by serology and 1.2% were positive in both tests. Serology-positive subjects were not at excess risk for future sick leave (OR, 1.06; 95% CI, .71-1.57). CONCLUSIONS: High amounts of SARS-CoV-2 virus, as determined using PCR Ct values, was associated with development of sickness in the next few weeks. Results support the concept that PCR Ct may be informative when testing for SARS-CoV-2. Clinical Trials Registration. NCT04411576.

Estimating Total Excess Mortality During a Coronavirus Disease 2019 Outbreak in Stockholm, Sweden.

Total excess mortality peaked during a coronavirus disease 2019 (COVID-19) outbreak in Stockholm, but 25% of these deaths were not recognized as COVID-19 related nor occurred in hospitals. Estimate of total excess mortality may give a more comprehensive picture of the total disease burden during a COVID-19 outbreak, and may facilitate managing future outbreaks.