L1-CAM in Mucinous Ovarian Carcinomas and Borderline Tumors: Impact on Tumor Recurrence and Potential Role in Tumor Progression.

Mucinous ovarian carcinoma (MOC) is a rare histotype of primary ovarian carcinoma. Frequent pathogenic molecular alterations include mutations in KRAS , TP53 , and overexpression of human epidermal growth factor receptor 2, but without having prognostic relevance. As L1-CAM (cell adhesion molecule) has previously shown prognostic relevance in other epithelial tumors of the female genital tract, we analyzed whether L1-CAM expression affected MOC prognosis. In addition, we investigated L1-CAM expression in mucinous borderline tumors (MBOTs) with and without adjacent MOC to identify its potential role in the pathogenesis of MOC. We examined a well-characterized collective of 39 MOCs by immunohistochemistry and compared their expression with clinicopathologic data. L1-CAM positivity was defined as any (even single-cell) positivity. Furthermore, we compared the L1-CAM expression in 20 MBOT regions adjacent to a MOC with that of 15 pure MBOTs. L1-CAM expression in MOC was significantly associated with recurrence, independent of tumor stage. Overall, 7/20 positive cases recurred versus 0/19 L1-CAM-negative cases ( P =0.032), showing a significant difference in time to progression. Furthermore, the presence of at least 1 defined molecular alteration (L1-CAM, aberrant p53, or human epidermal growth factor receptor 2) was found more frequently in the MBOT regions adjacent to a MOC (14/20) than in pure MBOTs (3/15) ( P =0.024). Expression of the tumor marker L1-CAM is frequent (51%) in MOC and is associated with tumor recurrence. The lack of L1-CAM may serve to characterize cases with a low risk of recurrence. Furthermore, the presence of specific molecular alterations in MBOTs is associated with adjacent carcinomas and may define potential pathways in tumor progression.

Implementing deep learning models for the classification of Echinococcus multilocularis infection in human liver tissue.

BACKGROUND: The histological diagnosis of alveolar echinococcosis can be challenging. Decision support models based on deep learning (DL) are increasingly used to aid pathologists, but data on the histology of tissue-invasive parasitic infections are missing. The aim of this study was to implement DL methods to classify Echinococcus multilocularis liver lesions and normal liver tissue and assess which regions and structures play the most important role in classification decisions. METHODS: We extracted 15,756 echinococcus tiles from 28 patients using 59 whole slide images (WSI); 11,602 tiles of normal liver parenchyma from 18 patients using 33 WSI served as a control group. Different pretrained model architectures were used with a 60-20-20% random splitting. We visualized the predictions using probability-thresholded heat maps of WSI. The area-under-the-curve (AUC) value and other performance metrics were calculated. The GradCAM method was used to calculate and visualize important spatial features. RESULTS: The models achieved a high validation and test set accuracy. The calculated AUC values were 1.0 in all models. Pericystic fibrosis and necrotic areas, as well as germinative and laminated layers of the metacestodes played an important role in decision tasks according to the superimposed GradCAM heatmaps. CONCLUSION: Deep learning models achieved a high predictive performance in classifying E. multilocularis liver lesions. A possible next step could be to validate the model using other datasets and test it against other pathologic entities as well, such as, for example, Echinococcus granulosus infection.

Internet searching on the head louse in the UK since the COVID-19 pandemic.

BACKGROUND: Wide-ranging restrictions on social and educational activities were imposed in 2020 in response to the COVID-19 pandemic. These likely influenced the population dynamics of the head louse. Close physical contact between human hosts is required for transmission of this ectoparasite. METHOD: Pre- and post-pandemic internet interest in the head louse in the UK was compared using Google Trends data from March 2017 to March 2022 and modeling using the Meta Prophet package. The influence of school holidays and school attendance was also investigated. RESULTS: There was a sharp decline in internet searching of the term "head louse" from March 2020 onwards coinciding with COVID-19 restrictions, and a large difference between pre- and post-pandemic search volumes. No influence of school holidays or attendance on internet searching on the head louse was found. CONCLUSION: The results suggest pandemic restrictions have had a large effect on head louse incidence.

Delirium in hospitalized COVID-19 patients: Predictors and implications for patient outcome.

INTRODUCTION: Delirium is recognized as a severe complication of coronavirus-disease-2019 (COVID-19). COVID-19-associated delirium has been linked to worse patient outcomes and is considered to be of multifactorial origin. Here we sought to evaluate the incidence and risk factors of delirium in hospitalized COVID-19 patients, along with its impact on clinical outcome. METHODS: Consecutive adult COVID-19 patients admitted to a tertiary academic referral hospital between March 1st and December 31st, 2020 were included. Potential risk factors for delirium were evaluated, including: age, gender, disease severity (as per the highest WHO grading reached during admission), laboratory parameters for infection and renal function (as per their most extreme values), and presence of comorbidities. To assess the relative strength of risk factors for predicting the occurrence of delirium, we performed a random-forest survival analysis. RESULTS: 347 patients with positive COVID-19 PCR test and median age 68.2 [IQR 55.5, 80.5] years were included. Of those, 79 patients (22.8%) developed delirium, 81 (23.3%) were transferred to ICU, 58 (16.7%) died. 163 (73.8%) patients were discharged home, 13 (5.9%) to another hospital, 32 (14.5%) to nursing homes, 13 (5.9%) to rehabilitation with an overall median admission-to-discharge time of 53 [IQR 14, 195] days. The strongest predictors for the occurrence of delirium were blood urea nitrogen (minimal depth value (MD): 3.33), age (MD: 3.75), disease severity (as captured by WHO grading; MD: 3.93), leukocyte count (MD: 4.22), the presence of a neurodegenerative history (MD: 4.43), ferritin (MD: 4.46) and creatinine (MD: 4.59) levels. CONCLUSION: The risk of delirium in COVID-19 can be stratified based on COVID-19 disease severity and-similar to delirium associated with other respiratory infections-the factors advanced age, neurodegenerative disease history, and presence of elevated infection and renal-retention parameters. Screening for these risk factors may facilitate early identification of patients at high-risk for COVID-19-associated delirium.

Time perception at resting state and during active motion: The role of anxiety and depression.

BACKGROUND: Time perception and motion intensity are interrelated factors that may influence symptom expression and severity in case of various psychiatric conditions, including anxiety and depression. AIMS: The present study aimed to 1) explore the associations between the intensity of physical activity, time perception, impulsivity, anxiety and depressive symptoms, and to 2) investigate the extent to which resting state motion intensity can be used to identify the assessed psychiatric conditions. METHODS: 20 healthy controls and 20 psychiatric patients (with either anxiety or depression-related diagnoses) were included in the study and filled out a questionnaire consisting of validated anxiety, depression and impulsivity measures. Time perception was measured by a computerized time production task, whereas motion intensity was analyzed by a motion capture and analysis software. Respondents were randomly assigned to an experimental (with active motion task) and non-experimental group (resting state conditions). Both subgroups were repeatedly assessed, in order to explore changes in motion intensity, time perception and psychiatric symptom levels. RESULTS: Random forest regression analysis identified the level of impulsivity, depression and anxiety as the strongest predictors of resting state motion intensity, while a path analysis model indicated that controls and psychiatric patients show different pathways regarding the connection between motion intensity changes, time production ratio alterations and symptom reduction. CONCLUSIONS: Our study implies the importance of distinguishing between clinical and subclinical severity of psychiatric symptoms when considering the association between motion intensity, time perception, anxiety and depression. Potential transdiagnostic relevance of resting state motion intensity is also addressed.

A PfSPZ vaccine immunization regimen equally protective against homologous and heterologous controlled human malaria infection.

Immunization with radiation-attenuated Plasmodium falciparum (Pf) sporozoites (SPZ) in PfSPZ Vaccine, has provided better vaccine efficacy (VE) against controlled human malaria infection (CHMI) with the same parasites as in the vaccine (homologous) than with genetically distant parasites (heterologous). We sought to identify an immunization regimen that provided similar VE against CHMI with homologous and heterologous Pf for at least 9 weeks in malaria-naïve adults. Such a regimen was identified in part 1 (optimization), an open label study, and confirmed in part 2 (verification), a randomized, double-blind, placebo-controlled study in which VE was assessed by cross-over repeat CHMI with homologous (PfNF54) and heterologous (Pf7G8) PfSPZ at 3 and 9-10 weeks. VE was calculated using Bayesian generalized linear regression. In part 1, vaccination with 9 × 105 PfSPZ on days 1, 8, and 29 protected 5/5 (100%) subjects against homologous CHMI at 3 weeks after the last immunization. In part 2, the same 3-dose regimen protected 5/6 subjects (83%) against heterologous CHMI at both 3 and 9-10 weeks after the last immunization. Overall VE was 78% (95% predictive interval: 57-92%), and against heterologous and homologous was 79% (95% PI: 54-95%) and 77% (95% PI: 50-95%) respectively. PfSPZ Vaccine was safe and well tolerated. A 4-week, 3-dose regimen of PfSPZ Vaccine provided similar VE for 9-10 weeks against homologous and heterologous CHMI. The trial is registered with ClinicalTrials.gov, NCT02704533.

Reporting of melanoma cell densities in the sentinel node refines outcome prediction.

INTRODUCTION: Sentinel node biopsy is a key procedure to predict prognosis in melanoma. In a prospective study we compare reporting on melanoma cell densities in cytospin preparations with semiquantitative histopathology for predicting outcome. PATIENTS AND METHODS: Sentinel nodes from 900 melanoma patients were bisected. One half of each node was disaggregated mechanically. The melanoma cell density (number of HMB45 positive cells per million lymphocytes with at least one cell showing morphological features of a melanoma cell) was recorded after examining two cytospins. For the second half the maximum diameter of metastasis was determined after haematoxylin and eosin (H&E) and immunohistological staining of three slides. RESULTS: Cytospins were positive for melanoma in 218 of 900 patients (24%). Routine pathology was positive in 111 of 900 (12%) patients. A more extensive pathological workup in cytospin-only positive patients led to a revised diagnosis (from negative to positive) in 23 of 101 patients (22.7%). We found a moderate but significant correlation between melanoma cell densities (determined in cytospins) and the maximum diameter of metastasis (determined by pathology) (rho = 0.6284, p < 0.001). At a median follow-up of 37 months (IQR 25-53 months) melanoma cell density (cytospins) (p < 0.001), thickness of melanoma (p = 0.008) and ulceration status (p = 0.026) were significant predictors for melanoma specific survival by multivariable testing and were all confirmed as key predictive factors by the random forest model. Maximum diameter of metastases, age and sex were not significant by multivariable testing (all p > 0.05). CONCLUSION: Recording melanoma cell densities by examining two cytospins accurately predicts melanoma outcome and outperforms semiquantitative histopathology.

Efficacy, T cell activation and antibody responses in accelerated Plasmodium falciparum sporozoite chemoprophylaxis vaccine regimens.

Repeated direct venous inoculation of Plasmodium falciparum sporozoites (PfSPZ) together with antimalarial chemoprophylaxis (PfSPZ-CVac) is the most potent way to induce sterile immunity against P. falciparum infection in malaria-naive volunteers. However, established schedules are complex and long. Here, we tested two accelerated three-dose schedules (28- and 10-day regimen) assessing efficacy by controlled human malaria infection (CHMI) against placebo, comparing vaccine-specific T cell and antibody responses by antigen-reactive T cell enrichment (ARTE) and protein microarray, respectively. Both regimens were similarly efficacious (67 and 63% vaccine efficacy) but different in the induction of vaccine-specific T cells and antibodies. The 10-day regimen resulted in higher numbers of antigen-specific CD4+ effector memory pro-inflammatory T cells and a broader antibody response compared with the 28-day regimen. Usually in nature, P. falciparum liver stage lasts about 6.5 days. The short vaccination-interval of the 10-day regimen prolongs the time of continuous exposure to liver-stage parasites, which may explain the stronger response. Besides dose and number of vaccinations, duration of liver-stage exposure is a factor to optimize PfSPZ-CVac immunogenicity.

Withholding or withdrawing life support in long-term neurointensive care patients: a single-centre, prospective, observational pilot study.

PURPOSE: Scarce evidence exists regarding end-of-life decision (EOLD) in neurocritically ill patients. We investigated the factors associated with EOLD making, including the group and individual characteristics of involved healthcare professionals, in a multiprofessional neurointensive care unit (NICU) setting. MATERIALS AND METHODS: A prospective, observational pilot study was conducted between 2013 and 2014 in a 10-bed NICU. Factors associated with EOLD in long-term neurocritically ill patients were evaluated using an anonymised survey based on a standardised questionnaire. RESULTS: 8 (25%) physicians and 24 (75%) nurses participated in the study by providing their 'treatment decisions' for 14 patients at several time points. EOLD was 'made' 44 (31%) times, while maintenance of life support 98 (69%) times. EOLD patterns were not significantly different between professional groups. The individual characteristics of the professionals (age, gender, religion, personal experience with death of family member and NICU experience) had no significant impact on decisions to forgo or maintain life-sustaining therapy. EOLD was patient-specific (intraclass correlation coefficient: 0.861), with the presence of acute life-threatening disease (OR (95% CI): 18.199 (1.721 to 192.405), p=0.038) and low expected patient quality of life (OR (95% CI): 9.276 (1.131 to 76.099), p=0.016) being significant and independent determinants for withholding or withdrawing life-sustaining treatment. CONCLUSIONS: Our findings suggest that EOLD in NICU relies mainly on patient prognosis and not on the characteristics of the healthcare professionals.

Social mobility and gonorrhoea in Germany during 2020.

OBJECTIVES: The incidence of STIs is likely to be related to levels of social activity and mobility. Novel datasets detailing levels of social activity were made widely available during the COVID-19 pandemic. These allow the relationship between activity and STI incidence to be examined. METHODS: The correlation between social activities and the reported number of gonorrhoea cases between March and December 2020 in Germany was studied. Regression through Autoregressive Integrated Moving Average (ARIMA) time series modelling identified those activities associated with case numbers. RESULTS: ARIMA regression identified a significant association with 'transit' activity within the Apple data and 'parks' within Google. CONCLUSIONS: This study illustrates the potential newly available measures of social activity provided for STI research. Reductions in STI incidence are likely to have occurred due to COVID-19 social restrictions. Although other studies report reductions in infectious diseases during this period, few examine the potential social factors mediating this. The results illustrate the continual need for sexual health services throughout the pandemic.

Forecasting the future number of pertussis cases using data from Google Trends.

BACKGROUND: Alternative methods could be used to enhance the monitoring and forecasting of re-emerging conditions such as pertussis. Here, whether data on the volume of Internet searching on pertussis could complement traditional modeling based solely on reported case numbers was assessed. METHODS: SARIMA models were fitted to describe reported weekly pertussis case numbers over a four-year period in Germany. Pertussis-related Google Trends data (GTD) was added as an external regressor. Predictions were made by the models, both with and without GTD, and compared with values within the validation dataset over a one-year and for a two-weeks period. RESULTS: Predictions of the traditional model using solely reported case numbers resulted in an RMSE (residual mean squared error) of 192.65 and 207.8, a mean absolute percentage error (MAPE) of 58.59 and 72.1, and a mean absolute error (MAE) 169.53 and 190.53 for the one-year and for the two-weeks period, respectively. The GTD expanded model achieved better forecasting accuracy (RMSE: 144.22 and 201.78), a MAPE 43.86, and 68.54 and a MAE of 124.46 and 178.96. Corrected Akaike Information Criteria also favored the GTD expanded model (1750.98 vs. 1746.73). The difference between the predictive performances was significant when using a two-sided Diebold-Mariano test (DM value: 6.86, p < 0.001) for the one-year period. CONCLUSION: Internet-based surveillance data enhanced the predictive ability of a traditionally based model and should be considered as a method to enhance future disease modeling.

Heterologous protection against malaria by a simple chemoattenuated PfSPZ vaccine regimen in a randomized trial.

Immunization with Plasmodium falciparum (Pf) sporozoites under chemoprophylaxis (PfSPZ-CVac) is the most efficacious approach to malaria vaccination. Implementation is hampered by a complex chemoprophylaxis regimen and missing evidence for efficacy against heterologous infection. We report the results of a double-blinded, randomized, placebo-controlled trial of a simplified, condensed immunization regimen in malaria-naive volunteers (EudraCT-Nr: 2018-004523-36). Participants are immunized by direct venous inoculation of 1.1 × 105 aseptic, purified, cryopreserved PfSPZ (PfSPZ Challenge) of the PfNF54 strain or normal saline (placebo) on days 1, 6 and 29, with simultaneous oral administration of 10 mg/kg chloroquine base. Primary endpoints are vaccine efficacy tested by controlled human malaria infection (CHMI) using the highly divergent, heterologous strain Pf7G8 and safety. Twelve weeks following immunization, 10/13 participants in the vaccine group are sterilely protected against heterologous CHMI, while (5/5) participants receiving placebo develop parasitemia (risk difference: 77%, p = 0.004, Boschloo's test). Immunization is well tolerated with self-limiting grade 1-2 headaches, pyrexia and fatigue that diminish with each vaccination. Immunization induces 18-fold higher anti-Pf circumsporozoite protein (PfCSP) antibody levels in protected than in unprotected vaccinees (p = 0.028). In addition anti-PfMSP2 antibodies are strongly protection-associated by protein microarray assessment. This PfSPZ-CVac regimen is highly efficacious, simple, safe, well tolerated and highly immunogenic.

A call to caution when hydroxychloroquine is given to elderly patients with COVID-19.

INTRODUCTION: Use of hydroxychloroquine in patients with coronavirus disease 2019 (COVID-19) was widespread and uncontrolled until recently. Patients vulnerable to severe COVID-19 are at risk of hydroxychloroquine interactions with co-morbidities and co-medications contributing to detrimental, including fatal, adverse treatment effects. METHODS: A retrospective survey was undertaken of health conditions and co-medications of patients with COVID-19 who were pre-screened for enrolment in a randomized, double-blind, placebo-controlled hydroxychloroquine multi-centre trial. RESULTS: The survey involved 305 patients [median age 71 (interquartile range 59-81) years]. The majority of patients (n = 279, 92%) considered for inclusion in the clinical trial were not eligible, mainly due to safety concerns caused by health conditions or co-medications. The most common were QT-prolonging drugs (n = 188, 62%) and haematologic/haemato-oncologic diseases (n = 39, 13%) which prohibited the administration of hydroxychloroquine. In addition, 165 (54%) patients had health conditions and 167 (55%) patients were on co-medications that did not prohibit the use of hydroxychloroquine but had a risk of adverse interactions with hydroxychloroquine. The most common were diabetes (n = 86, 28%), renal insufficiency (n = 69, 23%) and heart failure (n = 58, 19%). CONCLUSION: The majority of hospitalized patients with COVID-19 had health conditions or took co-medications precluding safe treatment with hydroxychloroquine. Therefore, hydroxychloroquine should be administered with extreme caution in elderly patients with COVID-19, and only in clinical trials.

Mobility and COVID-19 mortality across Scandinavia: A modeling study.

BACKGROUND: In response to COVID-19, the Swedish government imposed few travel and mobility restrictions. This contrasted with its Scandinavian neighbours which implemented stringent restrictions. The influence these different approaches had on mobility, and thus on COVID-19 mortality was investigated. METHODS: Datasets indicating restriction severity and community mobility were examined; Google's 'Community Movement Reports' (CMR) show activity at key location categories; the Oxford COVID-19 Government Response Tracker collates legislative restrictions into a 'Stringency Index' (SI). RESULTS: CMR mobility categories were negatively correlated with COVID-19 mortality. The strongest correlations were obtained by negatively time lagging mortality data, suggesting restrictions had a delayed influence. During the 'first wave' a model using SI (AIC 632.87) proved favorable to one using contemporaneous CMR data and SI (AIC 1193.84), or lagged CMR data and SI (AIC 642.35). Validation using 'second wave' data confirmed this; the model using SI solely again being optimal (RMSE: 0.2486 vs. 0.522 and 104.62). Cross-country differences were apparent in all models; Swedish data, independent of SI and CMR, proved significant throughout. There was a significant association for Sweden and the death number across models. CONCLUSION: SI may provide a broader, more accurate, representation of changes in movement in response to COVID-19 restrictions.

Alveolar Echinococcosis-A Challenging Task for the Hepatobiliary Surgeon.

(1) Background: Alveolar echinococcosis (AE) is an ultimately fatal disease, whose only curative treatment is surgery. Due to its late presentation extended liver resections are often necessary. The true benefit of extensive surgery has yet to be established; (2) Methods: We present a single center experience of 33 cases of Echinococcus multilocularis that have been treated at a high-volume hepatobiliary surgery center between 2004 and 2021. (3) Results: Of the 33 patients 24 patients underwent major liver resection (73%). In addition to the liver resection patients frequently underwent complex extrahepatic procedures such as lymphadenectomy (n = 21, 61%), vascular resections and reconstructions (n = 9, 27%) or resections and reconstruction of the extrahepatic bile duct (n = 11, 33%). Seven patients suffered from ≥ grade III complications (21%). Complete resection was achieved in 17 patients. Fourteen patients had R1 resections and two had macroscopic parasitic remnant (R2). Progressive disease was reported in three patients (The two R2 patients and one R1 resected patient). At a median follow-up of 54 months no mortality has occurred in our cohort; (4) Conclusions: Liver resection remains the gold standard for AE. Even in extensive disease the combination of complex resection and perioperative benzimidazoles can achieve favorable long-term outcomes.

Google Trends Data and COVID-19 in Europe: Correlations and model enhancement are European wide.

The current COVID-19 pandemic offers a unique opportunity to examine the utility of Internet search data in disease modelling across multiple countries. Most such studies typically examine trends within only a single country, with few going beyond describing the relationship between search data patterns and disease occurrence. Google Trends data (GTD) indicating the volume of Internet searching on 'coronavirus' were obtained for a range of European countries along with corresponding incident case numbers. Significant positive correlations between GTD with incident case numbers occurred across European countries, with the strongest correlations being obtained using contemporaneous data for most countries. GTD was then integrated into a distributed lag model; this improved model quality for both the increasing and decreasing epidemic phases. These results show the utility of Internet search data in disease modelling, with possible implications for cross country analysis.

Forecasting tuberculosis using diabetes-related google trends data.

Online activity-based data can be used to aid infectious disease forecasting. Our aim was to exploit the converging nature of the tuberculosis (TB) and diabetes epidemics to forecast TB case numbers. Thus, we extended TB prediction models based on traditional data with diabetes-related Google searches. We obtained data on the weekly case numbers of TB in Germany from June 8th, 2014, to May 5th, 2019. Internet search data were obtained from a Google Trends (GTD) search for 'diabetes' to the corresponding interval. A seasonal autoregressive moving average (SARIMA) model (0,1,1) (1,0,0) [52] was selected to describe the weekly TB case numbers with and without GTD as an external regressor. We cross-validated the SARIMA models to obtain the root mean squared errors (RMSE). We repeated this procedure with autoregressive feed-forward neural network (NNAR) models using 5-fold cross-validation. To simulate a data-poor surveillance setting, we also tested traditional and GTD-extended models against a hold-out dataset using a decreased 52-week-long period with missing values for training. Cross-validation resulted in an RMSE of 20.83 for the traditional model and 18.56 for the GTD-extended model. Cross-validation of the NNAR models showed a mean RMSE of 19.49 for the traditional model and 18.99 for the GTD-extended model. When we tested the models trained on a decreased dataset with missing values, the GTD-extended models achieved significantly better prediction than the traditional models (p < 0.001). The GTD-extended models outperformed the traditional models in all assessed model evaluation parameters. Using online activity-based data regarding diabetes can improve TB forecasting, but further validation is warranted.

The Relationship between Mobility and COVID-19 in Germany: Modeling Case Occurrence using Apple's Mobility Trends Data.

BACKGROUND: Restrictions on social interaction and movement were implemented by the German government in March 2020 to reduce the transmission of coronavirus disease 2019 (COVID-19). Apple's "Mobility Trends" (AMT) data details levels of community mobility; it is a novel resource of potential use to epidemiologists. OBJECTIVE: The aim of the study is to use AMT data to examine the relationship between mobility and COVID-19 case occurrence for Germany. Is a change in mobility apparent following COVID-19 and the implementation of social restrictions? Is there a relationship between mobility and COVID-19 occurrence in Germany? METHODS: AMT data illustrates mobility levels throughout the epidemic, allowing the relationship between mobility and disease to be examined. Generalized additive models (GAMs) were established for Germany, with mobility categories, and date, as explanatory variables, and case numbers as response. RESULTS: Clear reductions in mobility occurred following the implementation of movement restrictions. There was a negative correlation between mobility and confirmed case numbers. GAM using all three categories of mobility data accounted for case occurrence as well and was favorable (AIC or Akaike Information Criterion: 2504) to models using categories separately (AIC with "driving," 2511. "transit," 2513. "walking," 2508). CONCLUSION: These results suggest an association between mobility and case occurrence. Further examination of the relationship between movement restrictions and COVID-19 transmission may be pertinent. The study shows how new sources of online data can be used to investigate problems in epidemiology.

Predicting tick-borne encephalitis using Google Trends.

Data generated through public Internet searching offers a promising alternative source of information for monitoring and forecasting of infectious disease. Here future cases of tick-borne encephalitis (TBE) were predicted using traditional weekly case reports, both with and without Google Trends data (GTD). Data on the weekly number of acute, confirmed TBE cases in Germany were obtained from the Robert Koch Institute. Data relating to the volume of Internet searching on TBE was downloaded from the Google Trends website. Data were split into training and validation parts. A SARIMA (0,1,1) (1,1,1) [52] model was used to describe the weekly TBE case number time series. Google Trends Data was used as an external regressor in a second, as optimal identified SARIMA (4,1,1) (1,1,1) [52] model. Predictions for the number of future cases were made with both models and compared with the validation dataset. GTD showed a significant correlation with reported weekly case numbers of TBE (p < 0.0001). A comparison of forecasted values with reported ones resulted in an RMSE (residual mean squared error) of 0.71 for the model without Google search values, and an RMSE of 0.70 for the Google Trends values enhanced model. However, difference between predictive performances was not significant (Diebold Mariano test, p-value = 0.14).

First-in-human, Randomized, Double-blind Clinical Trial of Differentially Adjuvanted PAMVAC, A Vaccine Candidate to Prevent Pregnancy-associated Malaria.

BACKGROUND: Malaria in pregnancy has major impacts on mother and child health. To complement existing interventions, such as intermittent preventive treatment and use of impregnated bed nets, we developed a malaria vaccine candidate with the aim of reducing sequestration of asexual "blood-stage" parasites in the placenta, the major virulence mechanism. METHODS: The vaccine candidate PAMVAC is based on a recombinant fragment of VAR2CSA, the Plasmodium falciparum protein responsible for binding to the placenta via chondroitin sulfate A (CSA). Healthy, adult malaria-naive volunteers were immunized with 3 intramuscular injections of 20 µg (n = 9) or 50 µg (n = 27) PAMVAC, adjuvanted with Alhydrogel or glucopyranosyl lipid adjuvant in stable emulsion (GLA-SE) or in a liposomal formulation with QS21 (GLA-LSQ). Allocation was random and double blind. The vaccine was given every 4 weeks. Volunteers were observed for 6 months following last immunization. RESULTS: All PAMVAC formulations were safe and well tolerated. A total of 262 adverse events (AEs) occurred, 94 (10 grade 2 and 2 grade 3) at least possibly related to the vaccine. No serious AEs occurred. Distribution and severity of AEs were similar in all arms. PAMVAC was immunogenic in all participants. PAMVAC-specific antibody levels were highest with PAMVAC-GLA-SE. The antibodies inhibited binding of VAR2CSA expressing P. falciparum-infected erythrocytes to CSA in a standardized functional assay. CONCLUSIONS: PAMVAC formulated with Alhydrogel or GLA-based adjuvants was safe, well tolerated, and induced functionally active antibodies. Next, PAMVAC will be assessed in women before first pregnancies in an endemic area. CLINICAL TRIALS REGISTRATION: EudraCT 2015-001827-21; ClinicalTrials.gov NCT02647489.