PURPOSE:A subset of patients with human papillomavirus-positive oropharyngeal squamous cell carcinoma develops disease recurrence despite generally favorable outcomes. Reliable biomarkers for risk stratification remain lacking. We investigated whether comprehensive viral genomic profiling refines prognostic classification. EXPERIMENTAL DESIGN:Tumor samples from 100 patients with p16-positive and human papillomavirus DNA-positive oropharyngeal squamous cell carcinoma enrolled in two independent cohorts were analyzed using targeted viral capture sequencing. Viral genotype, sublineage, single-nucleotide variation, viral-host integration sites, viral structural variants, clonality, and viral copy number were characterized. Associations with cumulative incidence of progression, progression-free survival and overall survival were assessed at 60 months. RESULTS:Human papillomavirus 16 was detected in 94 tumors, of which 83 belonged to the HPV16_A1 sublineage. Within this sublineage, 20 tumors harbored strictly episomal viral genomes, whereas 63 exhibited integration and/or viral structural variants. No progression events occurred in the strictly episomal HPV16_A1 subgroup, while 12 occurred among tumors HPV16_A1 with integration and/or structural variant. At 60 months, no progression events were observed in strictly episomal HPV16_A1 tumors, compared with a 23.1% cumulative incidence of progression in HPV16_A1 tumors with integration and/or structural variant. Previously reported high-risk single-nucleotide variants and a novel upstream regulatory region variant were associated with worse progression-free survival. Integration sites were enriched in open chromatin and promoter regions and clustered within viral E2 and E4 genes. CONCLUSIONS:Within human papillomavirus 16 A1 tumors, viral genomic architecture defines clinically distinct subgroups. Strictly episomal (WT) genomes identify a low-risk population, whereas integration and structural variants characterize higher-risk disease.

Background: If hospital Clinical Data Warehouses are to address today's focus in personalized medicine, they need to be able to track patients longitudinally and manage the large data sets generated by whole genome sequencing, RNA analyses, and complex imaging studies. Current Clinical Data Warehouses address neither issue. This paper reports on methods to enrich current systems by providing provenance data allowing patient histories to be followed longitudinally and managing the linking and versioning of large data sets from whatever source. The methods are open source and applicable to any clinical data warehouse system, whether data schema it uses. Method: We introduce gITOMMIx, an approach that overcomes these limitations, and illustrate its usefulness in the management of medical omics data. gITOMMIx relies on (i) a file versioning system: git, (ii) an extension that handles large files: git-annex, (iii) a provenance knowledge graph: PROV-O, and (iv) an alignment between the git versioning information and the provenance knowledge graph. Results: Capabilities inherited from git and git-annex enable retracing the history of a clinical interpretation back to the patient sample, through supporting data and analyses. In addition, the provenance knowledge graph, aligned with the git versioning information, enables querying and browsing provenance relationships between these elements. Conclusion: gITOMMIx adds a provenance layer to CDWs, while scaling to large files and being agnostic of the CDW system. For these reasons, we think that it is a viable and generalizable solution for omics clinical studies.

Introduction: The implication of viruses in human cancers, as well as the emergence of next generation sequencing has permitted to investigate further their role and pathophysiology in the development of this disease. One such mechanism is the integration of portions of viral genomes in the human genome, as well as the specific action of viral oncogenes.inding integration sites and preserved oncogenes is still relying on heavy manual intervention. Methods: We developed an analysis and interpretation pipeline to determine viral insertions. Using data from directed viral capture, the pipeline conducts a crude genotyping phase to select reference viral genomes, identifies chimeric reads, extracts the putative human sequences to locate in the human reference genome, scores and ranks candidate junctions, and exports tabular and visual results. Results: We leverage common bioinformatics tools (bowtie2, samtools, blat), and a dedicated filtering and ranking algorithm, implemented in R, to infer candidate junctions and insertions. Static results (tables, figures) are produced, as well as an interactive interpretation tool developed as a shiny web app. Discussion: We validated this pipeline against published results of HPV, HBV, and AAV2 insertions and show good information retrieval.

Medical reports are key elements to guarantee the quality, and continuity of care but their quality remains an issue. Standardization and structuration of reports can increase their quality, but are usually based on expert opinions. Here, we hypothesize that a structured model of medical reports could be learnt using machine learning on retrospective medical reports extracted from clinical data warehouses (CDW). To investigate our hypothesis, we extracted breast cancer operative reports from our CDW. Each document was preprocessed and split into sentences. Clustering was performed using TFIDF, Paraphrase or Universal Sentence Encoder along with K-Means, DBSCAN, or Hierarchical clustering. The best couple was TFIDF/K-Means, providing a sentence coverage of 89 % on our dataset; and allowing to identify 7 main categories of items to include in breast cancer operative reports. These results are encouraging for a document preset creation task and should then be validated and implemented in real life.

Objectives: Risk of reinfection with SARS-CoV-2 among health-care workers (HCWs) is unknown. We assessed the incidence rate of SARS-CoV-2 reinfection in the real-life setting of a longitudinal observational cohort of HCWs from the Hopital Europeen Georges Pompidou, Assistance Publique-Hopitaux de Paris, France, during the first and second waves of COVID-19 epidemic. Methods: From March to December 2020, HCWs were subjected to molecular and serology testing of SARS-CoV-2. Reinfection was defined as a positive test result during the first wave, either by serology or PCR, followed by a positive PCR during the second wave. Evolution of COVID-19 status of HWCs was assessed by a Sankey diagram. Results: A total of 7765 tests (4579 PCR and 3186 serology) were carried out and 4168 HCWs had at least one test result during the follow-up period with a positivity rate of 15.9%. No case of reinfection during the second wave could be observed among 102 positive HCWs of the first wave, nor among 175 HCWs found positive by PCR during the second wave who were negative during the first wave. Conclusions: SARS-CoV-2 reinfection was not observed among HCWs, suggesting a protective immunity against reinfection that lasts at least 8 months post infection.

Background Approximately 15-30% of hospitalized coronavirus disease 2019 (COVID-19) patients develop acute respiratory distress syndrome, systemic tissue injury, and/or multi-organ failure leading to death in around 45% of cases. There is a clear need for biomarkers that quantify tissue injury, predict clinical outcomes, and guide the clinical management of hospitalized COVID-19 patients. Methods We herein report the quantification by droplet-based digital polymerase chain reaction (ddPCR) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNAemia and the plasmatic release of a ubiquitous human intracellular marker, the ribonuclease P (RNase P) in order to evaluate tissue injury and cell lysis in the plasma of 139 COVID-19 hospitalized patients at admission. Results We confirmed that SARS-CoV-2 RNAemia was associated with clinical severity of COVID-19 patients. In addition, we showed that plasmatic RNase P RNAemia at admission was also highly correlated with disease severity (P < .001) and invasive mechanical ventilation status (P < .001) but not with pulmonary severity. Altogether, these results indicate a consequent cell lysis process in severe and critical patients but not systematically due to lung cell death. Finally, the plasmatic RNase P RNA value was also significantly associated with overall survival. Conclusions Viral and ubiquitous blood biomarkers monitored by ddPCR could be useful for the clinical monitoring and the management of hospitalized COVID-19 patients. Moreover, these results could pave the way for new and more personalized circulating biomarkers in COVID-19, and more generally in infectious diseases, specific from each patient organ injury profile. Blood biomarkers for the clinical monitoring and the management of hospitalized coronavirus disease 2019 (COVID-19) patients are clearly needed. Herein, we report the particular usefulness of ubiquitous circulating RNA monitoring by droplet-based digital polymerase chain reaction (ddPCR) as a predictive and prognosis biomarker for hospitalized COVID19 patients.

The mechanisms that allowed for the SARS-CoV-2 B.1.1.7 variant to rapidly outcompete pre-existing variants in many countries remain poorly characterized. Here, we analyzed viral release, anti-SARS-CoV-2 antibodies and cytokine production in a retrospective series of 427 RTqPCR+ nasopharyngeal swabs collected in COVID-19 patients harbouring either non-B.1.1.7 or B.1.17 variants. We utilized a novel rapid assay, based on S-Fuse-T reporter cells, to quantify infectious SARS-CoV-2. With both non-B.1.1.7 and B.1.1.7 variants, viral titers were highly variable, ranging from 0 to >106 infectious units, and correlated with viral RNA levels. Lateral flow antigenic rapid diagnostic tests (RDTs) were positive in 96% of the samples harbouring infectious virus. About 67 % of individuals carried detectable infectious virus within the first two days after onset of symptoms. This proportion decreased overtime, and viable virus was detected up to 14 days. Samples containing anti-SARS-CoV-2 IgG or IgA did not generally harbour infectious virus. The proportion of individuals displaying viable virus or being RDT-positive was not higher with B.1.1.7 than with non- B.1.1.7 variants. Ct values were slightly but not significantly lower with B.1.1.7. The variant was characterized by a fast decrease of infectivity overtime and a marked release of 17 cytokines (including IFN-b, IP-10, IL-10 and TRAIL). Our results highlight differences between non-B.1.1.7 and B.1.1.7 variants. B.1.1.7 is associated with modified viral decays and cytokine profiles at the nasopharyngeal mucosae during symptomatic infection.

Background: The increasing complexity of data streams and computational processes in modern clinical health information systems makes reproducibility challenging. Clinical natural language processing (NLP) pipelines are routinely leveraged for the secondary use of data. Workflow management systems (WMS) have been widely used in bioinformatics to handle the reproducibility bottleneck. Objective: To evaluate if WMS and other bioinformatics practices could impact the reproducibility of clinical NLP frameworks. Materials and Methods: Based on the literature across multiple researcho fields (NLP, bioinformatics and clinical informatics) we selected articles which (1) review reproducibility practices and (2) highlight a set of rules or guidelines to ensure tool or pipeline reproducibility. We aggregate insight from the literature to define reproducibility recommendations. Finally, we assess the compliance of 7 NLP frameworks to the recommendations. Results: We identified 40 reproducibility features from 8 selected articles. Frameworks based on WMS match more than 50% of features (26 features for LAPPS Grid, 22 features for OpenMinted) compared to 18 features for current clinical NLP framework (cTakes, CLAMP) and 17 features for GATE, ScispaCy, and Textflows. Discussion: 34 recommendations are endorsed by at least 2 articles from our selection. Overall, 15 features were adopted by every NLP Framework. Nevertheless, frameworks based on WMS had a better compliance with the features. Conclusion: NLP frameworks could benefit from lessons learned from the bioinformatics field (eg, public repositories of curated tools and workflows or use of containers for shareability) to enhance the reproducibility in a clinical setting.

Archival tissue samples collected longitudinally from a patient who died from HPV16-induced high-grade anal intraepithelial squamous cell carcinoma with vertebral HPV16-positive metastasis were retrospectively analyzed by the Capture-HPV method (Capt-HPV) followed by Next-Generation Sequencing (NGS). Full length nucleotide sequences of the same HPV16 were identified from the initial and second anal biopsy samples, from plasma sample and from vertebral metastasis biopsy. Remarkably, HPV was episomal in each sample. The HPV genome sequence was closest to the HPV16 Qv18158E variant subtype (A1 lineage) exhibiting base substitutions and deletions in 7 and 2 HPV loci, respectively. In conclusion, the powerful Capt-HPV followed by NGS allows evidencing the detailed cartography of tumoral and circulating HPV DNA, giving rise to a unique and unexpected episomal virus molecular status in a context of aggressive carcinoma, underlying the importance of HPV status and its association with clinical features for further prospective studies.

BackgroundThe dynamics of SARS-CoV-2 alpha variant shedding and immune responses at the nasal mucosa remain poorly characterised.MethodsWe measured infectious viral release, antibodies and cytokines in 426 PCR+ nasopharyngeal swabs from individuals harboring non-alpha or alpha variants.FindingsWith both lineages, viral titers were variable, ranging from 0 to >106 infectious units. Rapid antigenic diagnostic tests were positive in 94% of samples with infectious virus. 68 % of individuals carried infectious virus within two days after onset of symptoms. This proportion decreased overtime. Viable virus was detected up to 14 days. Samples containing anti-spike IgG or IgA did not generally harbor infectious virus. Ct values were slightly but not significantly lower with alpha. This variant was characterized by a fast decrease of infectivity overtime and a marked release of 13 cytokines (including IFN-b, IP-10 and IL-10).InterpretationThe alpha variant displays modified viral decay and cytokine profiles at the nasopharyngeal mucosae during symptomatic infection.FundingThis retrospective study has been funded by Institut Pasteur, ANRS, Vaccine Research Institute, Labex IBEID, ANR/FRM and IDISCOVR, Fondation pour la Recherche Médicale.

This paper presents an approach for tuning IoT activity in order to control the message transmission frequency to reduce energy consumption. More precisely, instead of letting an IoT sending out data periodically and monotonically, the approach allows the determination of wake-up, messages transmission and reception periods, when events occur at suitable epochs. In other terms, energy consumption is reduced by avoiding useless wake-up to send data during slack periods. The approach uses the mathematical framework for discreet event system Max-Plus algebra. To illustrate the approach, a use case and numerical example is provided.

Nasopharyngeal swab is the reference sampling method to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as recommended by the World Health Organization (WHO) (1). However, nasal specimens may have a slightly lower sensitivity than nasopharyngeal specimens (2, 3). We herein validated an alternative procedure to collect nasal secretions with a swab routinely used in medical bacteriology for which there is no risk of supply disruption in order to perform the molecular diagnosis of SARS-CoV-2 infection.

Background. Coronavirus disease 2019 (COVID-19) is a global public health problem that has already caused more than 662 000 deaths worldwide. Although the clinical manifestations of COVID-19 are dominated by respiratory symptoms, some patients present other severe damage such as cardiovascular, renal and liver injury, and/or multiple organ failure, suggesting a spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in blood. Recent ultrasensitive polymerase chain reaction (PCR) technology now allows absolute quantification of nucleic acids in plasma. We intend to use the droplet-based digital PCR technology to obtain sensitive detection and precise quantification of plasma SARS-CoV-2 viral load (SARS-CoV-2 RNAemia) in hospitalized COVID-19 patients. Methods. Fifty-eight consecutive COVID-19 patients with pneumonia 8 to 12 days after onset of symptoms and 12 healthy controls were analyzed. Disease severity was categorized as mild to moderate in 17 patients, severe in 16, and critical in 26. Plasma SARS-CoV-2 RNAemia was quantified by droplet digital Crystal Digital PCR next-generation technology (Stilla Technologies, Villejuif, France). Results. Overall, SARS-CoV-2 RNAemia was detected in 43 (74.1%) patients. Prevalence of positive SARS-CoV-2 RNAemia correlated with disease severity, ranging from 53% in mild-to-moderate patients to 88% in critically ill patients (P =.036). Levels of SARS-CoV-2 RNAemia were associated with severity (P =.035). Among 9 patients who experienced clinical deterioration during follow-up, 8 had positive SARS-CoV-2 RNAemia at baseline, whereas only 1 critical patient with undetectable SARS-CoV-2 RNAemia at the time of analysis died at day 27. Conclusion. SARS-CoV-2 RNAemia measured by droplet-based digital PCR constitutes a promising prognosis biomarker in COVID-19 patients.

Recently, both the WHO/IARC (World Health Organisation/International Agency for Research on Cancer) and the American Joint Committee on Cancer (AJCC) have classified the oropharyngeal squamous cell carcinoma (OPSCC) on the basis of HPV status. For this purpose, the WHO/IARC recommended direct molecular HPV testing. In practice, formalin-fixed, paraffin-embedded (FFPE) biopsy specimens are frequently the only available samples. We herein compared in parallel two commercially available molecular assays that were firstly designed for cervical HPV detection and genotyping: Inno-Lipa ® HPV genotyping extra II assay (Fujirebio, Gent, Belgium) (IL) and Anyplex TM II HPV 28 (Seegene, Seoul, South Korea) (AP28). Both assays were carried out on the same DNA extracts obtained from prospectively collected FFPE biopsies from OPSCC origin and results were compared. A total of 55 samples were tested. By IL assay, chosen as reference assay, 27 (49.1%) biopsies were positive for HPV16, 10 (18.2%) were positive for HPV but negative for HPV16, and 18 (32.7%) were negative for HPV. A valid result with AP28 was obtained for 51 biopsy samples (92.7%). Among 37 HPV-positive samples by IL, 33 (89.2%) were positive by AP28. The agreement between both assays was good (Cohen’s κ = 0.78). Among the six discrepancies between assays, always associated with low HPV16 viral load, four biopsies positive for HPV16 by IL could not be detected by AP28. Taken together, these observations demonstrate that both assays could be used in routine for HPV detection and genotyping on FFPE-biopsy samples of head and neck tumour.

A significant part of medical knowledge is stored as unstructured free text. However, clinical narratives are known to contain duplicated sections due to clinicians' copy/paste parts of a former report into a new one. In this study, we aim at evaluating the duplications found within patient records in more than 650,000 French clinical narratives. We adapted a method to identify efficiently duplicated zones in a reasonable time. We evaluated the potential impact of duplications in two use cases: the presence of (i) treatments and/or (ii) relative dates. We identified an average rate of duplication of 33%. We found that 20% of the document contained drugs mentioned only in duplicated zones and that 1.45% of the document contained mentions of relative dates in duplicated zone, that could potentially lead to erroneous interpretation. We suggest the systematic identification and annotation of duplicated zones in clinical narratives for information extraction and temporal-oriented tasks.

We aimed to determine whether pretherapeutic assessment of HPV circulating tumoral DNA (HPV ctDNA) by droplet‐based digital PCR (ddPCR) could constitute a predictive and prognostic biomarker for HPV‐associated oropharyngeal squamous cell carcinoma (OPSCC). A mono‐institutional prospective biomarker study on 66 patients with p16+/HPV16‐positive oropharyngeal squamous cell carcinoma (OPSCC) was conducted in European Georges Pompidou Hospital, Paris, France. Blood samples were collected at the time of diagnosis before any treatment. Optimized digital PCR assays were used to quantify HPV16 ctDNA. Forty‐seven (71%) patients showed a positive pretherapeutic HPV ctDNA at time of diagnosis. Interestingly, the quantity of HPV16 ctDNA at baseline, as assessed by ddPCR, was significantly correlated with the T/N/M status or OPSCC stages according to the 2018 new staging criteria for high‐risk human papillomavirus (HR HPV) related OPSCC from American Joint Committee on Cancer (AJCC). Moreover, all recurrences and the majority (83%) of death reported events occurred in patients with positive HPV16 ctDNA at baseline. Finally, when posttreatment blood samples were available ( n = 6), the kinetic of pretreatment/posttreatment HPV16 ctDNA was clearly associated with treatment success or failure. HPV ctDNA monitoring by ddPCR could constitute a useful and noninvasive dynamic biomarker to select HR HPV‐related OPSCC patients eligible for potential treatment de‐escalation and to monitor treatment response.

Objective To determine the postoperative attempted and completed suicide rates after subthalamic nucleus deep brain stimulation (STN-DBS) in a single-center cohort and to determine factors associated with attempted and completed suicide. Methods We retrospectively included all patients with Parkinson disease (PD) who underwent bilateral STN-DBS surgery at the Grenoble University Hospital between 1993 and 2016. For each patient who committed or attempted suicide, 2 patients with PD with STN-DBS without any suicidal behaviors were matched for age (±1 year), sex, and year of surgery (±2 years). Clinical data were collected from medical records. Detailed preoperative and postoperative neuropsychological evaluations, including frontal and Beck Depression Inventory (BDI) scores, were gathered. Results A total of 534 patients with PD were included. Completed and attempted suicide percentages were 0.75% (4 of 534) and 4.11% (22 of 534), respectively. The observed suicide rate in the first postoperative year (187.20 of 100,000 per year, 1 of 534) was higher than the expected National Observatory on Suicide Risks rate adjusted for age and sex (standardized mortality ratio 8.1). This rate remained similar over the second and third postoperative years. In a comparison of the 26 patients completing/attempting suicide and the 52 controls, the first group showed more frequent history of suicidal ideation/suicide attempts and psychotic symptoms, higher percentage of family psychiatric history, higher psychiatric medication use, and higher preoperative frontal and BDI scores on neuropsychological evaluations. Conclusions Suicide behaviors can occur after STN-DBS, especially during the first 3 years. A careful multidisciplinary assessment and long-term follow-up are recommended to recognize and treat this potentially preventable risk for mortality.

The role of human papillomavirus (HPV) in anal squamous cell carcinoma (ASCC) carcinogenesis has been clearly established, involving the expression of viral oncoproteins and optional viral DNA integration into the host genome. In this article, we describe the various mechanisms and sites of HPV DNA insertion and assess their prognostic and predictive value in a large series of patients with HPV-positive ASCC with long-term follow-up. We retrospectively analyzed 96 tumor samples from 93 HPV-positive ASCC patients using the Capture-HPV method followed by Next-Generation Sequencing, allowing determination of HPV genotype and identification of the mechanisms and sites of viral genome integration. We identified five different mechanistic signatures of HPV insertions. The distribution of HPV signatures differed from that previously described in HPV-positive cervical carcinoma (p < 0.001). In ASCC samples, the HPV genome more frequently remained in episomal form (45.2%). The most common signature of HPV insertion was MJ-SC (26.9%), i.e., HPV-chromosomal junctions scattered at different loci. Functionally, HPV integration signatures were not associated with survival or response to treatment, but were associated with viral load (p = 0.022) and PIK3CA mutation (p = 0.0069). High viral load was associated with longer survival in both univariate (p = 0.044) and multivariate (p = 0.011) analyses. Finally, HPV integration occurred on most human chromosomes, but intragenic integration into the NFIX gene was recurrently observed (n = 4/51 tumors). Overall, the distribution of mechanistic signatures of HPV insertions in ASCC was different from that observed in cervical carcinoma and was associated with viral load and PIK3CA mutation. We confirmed recurrent targeting of NFIX by HPV integration, suggesting a role for this gene in ASCC carcinogenesis.

Autonomous Vehicles (AV) communications promise to increase roadway safety by providing each vehicle with 360-degree situational awareness of other vehicles in proximity, and by complementing On Board Unit (OBU) and sensors such as radar or camera in detecting imminent crash scenarios. These vehicles provide communication services among one another (V2V) or with Road Side Infrastructure (V2I). Vehicular Ad Hoc Networks (VANETs) employ multichannel to provide a variety of safety and non-safety applications. Safety applications necessitate appropriate and reliable transmissions, while non-safety applications require performance and high speed. Broadcasting of Basic Safety Messages (BSM) is one of the fundamental services in today's autonomous vehicles. With the excitement related to the revolution in technology comes the challenge to make these systems dependable to ensure the safety of the consumer and the public. We focused in this paper, on the reliability of AV as a whole. Our scientific approach was structured with methods that combine qualitative approaches and quantitative methods based on the data published by the California Department of Motor Vehicles concerning the accidents and the disengagement reports of AV. Evaluating these problems leads to a sensitivity analysis related to reliability parameters, which helps further innovation in vehicle automation and automobile engineering. Moreover, an analytical model for the reliability of BSM communication was proposed.