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Program management (PM) complexity depends on the budget size and program types. In general, the program types can be classified into three categories, namely, defense, commercial, and civilian types. This chapter presents and discusses an approach for integrating the PM discipline areas with emerging data science and decision science1 (DDS) for any program type. Additionally, we describe the key PM areas and present a corresponding generalized model consists of a list of multiple PM discipline areas that can be tailored for any program types. To demonstrate the PM-DDS integration approach, we focus on three key PM areas and corresponding PM discipline areas related to schedule, cost, and risk management. These three discipline areas are analyzed to identify appropriate program elements that can be enhanced using existing DDS technology enablers (TEs). We also propose a flexible PM-DSS integration framework by leveraging existing machine learning operations (MLOps) framework. The proposed integration framework is expected to allow for enhancing the program planning and execution by reducing the program risk using a wide range of DDS TEs, including big data analytics, artificial intelligence, machine learning, deep learning, neural networks, and artificial intelligent.

International audience; OBJECTIVES: To describe the investigation, follow-up, management and outcomes in a cohort of chronic kidney disease and kidney transplant recipients exposed to a case of pulmonary tuberculosis. METHODS: Contacts were investigated following a concentric circles approach and followed-up according to their level of priority. In those with an evidence of latent tuberculous infection, treatment decision was based on the level of exposure, individual vulnerability, as well as the results of an interferon-gamma release assay. RESULTS: 130 patients with chronic kidney disease and 180 kidney transplant recipients were identified as contacts and followed-up over a two-year period.Only few vulnerable high-priority contacts received an anti-tuberculosis treatment, including the 2 (100%)highly exposed patients in circle 1, 11/78(14.1%)chronic kidney disease patients and 4/142 (2.8%) kidney transplant recipients in circle 2, and10/52 (19.2%) chronic kidney disease patients and 2/36 (5.6%) kidney transplant recipients in circle 3;all having a positive interferon-gamma release assay result. No incident case of tuberculosis disease occurred. CONCLUSIONS: These findings suggest that latent tuberculosis treatment, as recommended in European guidelines, might be reasonably avoided in vulnerable high-priority contacts of circle 2 with a negative interferon-gamma release assay in countries with low prevalence of tuberculosis.

Synchytrium endobioticum (Schilb.) Perc. is a chytrid fungus causing potato wart disease and is one of the most important quarantine diseases on cultivated potato. Infected host tissues develop warts rendering the crop unmarketable. Resting spores, that can remain viable and infectious for decades, are formed in warted tissues and are released into the surrounding soil when host tissue decays.To better understand the pathogen’s diversity and to potentially uncover pathways of migrations and introduction events, molecular characterization was performed on the historical S. endobioticum resting spore collection of the Dutch National Plant Protection Organization. Mitochondrial genomes were assembled and annotated, and four novel structural variants were identified from these materials with intronic presence-absence variation in cox1 or cob genes and structural variation in the dpoB – TIR region. Several fungal isolates were shown to contain mixtures of structural variants. We analyzed the mitogenomic sequences obtained from recent potato wart disease findings in Canada and the Netherlands in the context of the historical materials and found that fungal isolates from the new Dutch outbreak contained a specific mixture of mitogenomic variants previously not observed in the Netherlands. Based on the mitogenomic profile, pathotype 38(Nevşehir) was suspected which was later verified with the Spieckermann bioassay. To further facilitate dissemination of data and interactive visual analytics we created a public Nextstrain webpage with S. endobioticum mitogenomic sequences and associated metadata on their geographic origin, pathotype identity and (mixture) of mitogenomic variants (https://nextstrain.nrcnvwa.nl/Sendo).

International audience

Resume Le traitement chirurgical des fuites spontanees de liquide cerebro-rachidien releve de nos jours d’une prise en charge otorhinolaryngologique car la reparation par voie endoscopique endonasale, moins invasive, est preferee a la craniotomie. Cependant, la fuite spontanee du liquide cerebro-rachidien est souvent le symptome d’une pathologie sous-jacente : l’hypertension intracrânienne idiopathique, qui depasse le champ d’expertise traditionnel de l’otorhinolaryngologiste. La chirurgie est une etape necessaire mais ne doit pas occulter la charge de l’hypertension intracrânienne sous-jacente. Celle-ci reste complexe et necessite une collaboration multidisciplinaire : otorhinolaryngologiste, ophtalmologiste, neurologue, neurochirurgien, radiologue, nutritionniste, endocrinologue et psychotherapeute. Cette mise au point vise a detailler la prise en charge multidisciplinaire a laquelle tout otorhinolaryngologiste doit etre attentif avant et apres reparation des fuites spontanees de liquide cerebro-rachidien.

Author(s): Wang, Yilun; Nguyen, Uyen-Sa DT; Lane, Nancy E; Lu, Na; Wei, Jie; Lei, Guanghua; Zeng, Chao; Zhang, Yuqing | Abstract: ObjectiveTo assess the relation of symptomatic knee osteoarthritis (OA), knee pain, and radiographic knee OA to All-cause mortality and to identify mediators in the causal pathway.MethodsParticipants from the Osteoarthritis Initiative were divided into 4 groups: 1) symptomatic knee OA (i.e., both radiographic knee OA [Kellgren/Lawrence grade ≥2] and knee pain); 2) knee pain only; 3) radiographic knee OA only; and 4) neither radiographic knee OA nor knee pain. We examined the relation of knee OA status to All-cause mortality using a multivariable Cox proportional hazards model and assessed the extent to which the association was mediated by disability, physical component summary (PCS) and mental component summary (MCS) scores for quality of life (QoL), and use of oral pain-relief medications (i.e., nonsteroidal antiinflammatory drugs and opioids).ResultsAmong 4,796 participants, 282 died over the 96-month follow-up period. Compared with those with neither radiographic knee OA nor knee pain, multivariable-adjusted hazard ratios (HRs) of mortality were 2.2 (95% confidence interval [95% CI] 1.6-3.1) for symptomatic knee OA, 0.9 (95% CI 0.6-1.4) for knee pain only, and 2.0 (95% CI 1.4-2.9) for radiographic knee OA only, respectively. Indirect effects (HRs) of symptomatic knee OA on mortality via disability and PCS of QoL were 1.1 (95% CI 1.0-1.4) and 1.2 (95% CI 1.0-1.4), respectively. No apparent mediation effect was observed through either MCS of QoL or oral pain-relief medications use.ConclusionParticipants with either symptomatic or radiographic knee OA were at an increased risk of All-cause mortality. Increased risk of mortality from symptomatic knee OA was partially mediated through its effect on disability and PCS of QoL.

Resume Le strabisme est une pathologie frequente (estimee a 2 a 3 % de la population pediatrique) et la plupart du temps de bon pronostic. Deux etiologies urgentes sont a eliminer : un strabisme resultant d’une paralysie oculomotrice et un strabisme secondaire a une pathologie oculaire ou strabisme « sensoriel » (par exemple lie a une cataracte, un retinoblastome…). Le principal risque du strabisme, quelle que soit son etiologie, est l’amblyopie, d’autant plus grand que le strabisme est constant non alternant et devant un microstrabisme de diagnostic souvent tardif. Une consultation avec un ophtalmologiste est necessaire devant tout vrai strabisme pour realiser un fond d’œil, une refraction sous cycloplegie et determiner la suite de la prise en charge adaptee au type de strabisme et a la presence ou non d’une amblyopie.

Multiaccess edge computing (MEC) enables autonomous vehicles to handle time-critical and data-intensive computational tasks for emerging Internet-of-Vehicles (IoV) applications via computation offloading. However, a massive amount of data generated by colocated vehicles is typically redundant, introducing a critical issue due to limited network bandwidth. Moreover, on the edge server side, these computation-intensive tasks further impose severe pressure on the resource-finite MEC server, resulting in low-performance efficiency of applications. To solve these challenges, we model the data redundancy and collaborative task computing scheme to efficiently reduce the redundant data and utilize the idle resources in nearby MEC servers. First, the data redundancy problem is formulated as a set-covering problem according to the spatiotemporal coverage of captured images. Next, we exploit the submodular optimization technique to design an efficient algorithm to minimize the number of images transferred to the MEC servers without degrading the quality of IoV applications. To facilitate the task execution in the MEC server, we then propose a collaborative task computing scheme, where an MEC server intentionally encourages nearby resource-rich MEC servers to participate in a collaborative computing group. Accordingly, a cost model is formulated as an optimization problem, the objective of which is to prompt the MEC server to judiciously allocate computing tasks to nearby MEC servers with the goal of achieving the minimal cost while the latency of tasks is guaranteed. Experimental results show that the proposed scheme can efficiently mitigate data redundancy, conserve network bandwidth consumption, and achieve the lowest cost for processing tasks.

Multi-access edge computing (MEC) can improve the users’ computational capacity and battery life by moving computing services to the network edge. In addition, data-content caching on a MEC server improves the user quality of experience and decreases the backhaul network congestion. Moreover, non-orthogonal multiple access (NOMA) has recently been implemented to increase network throughput and capacity. Combining these techniques can improve the user performance and benefit the network. This paper investigates a combined computational offloading and data-content caching problem for NOMA-MEC systems. The aim was to achieve the minimum total completion latency of all users by jointly optimizing the offloading decision, caching strategy, computational resource, and power allocation. This satisfies the constraints within the scope of the potential violation for energy consumption, offloading decision, and the computation and storage capacity of the MEC server. The formulated problem is a mixed-integer non-linear programming and a non-convex problem. To solve this challenging problem, a block successive upper-bound minimization method was implemented to obtain efficient solutions. Numerous simulation results were presented to demonstrate the convergence and efficacy of the proposed algorithm. Compared with other schemes of all-offloading, local-only, and equal resources, our proposed algorithm can approximately reduce the total completion latency by 17.68%, 26.02%, and 70.98%.

The stem and bulb nematode Ditylenchus dipsaci is a destructive nematode pest on many crops and is internationally quarantined in many countries, whereas Ditylenchus weischeri, only known to infect a weed plant (Cirsium arvense), is an unregulated nematode species with no known economic importance. In this study, we used comparative genomics to identify multiple gene regions and developed novel real-time PCR assays for the detection of D. dipsaci and D. weischeri. We sequenced the genomes of two mixed-stage nematode populations of D. dipsaci and two mixed-stage nematode populations of D. weischeri. The assembled genomes of D. dipsaci were 228.2 Mb and 239.5 Mb, and the genomes of D. weischeri were 177.0 Mb and 196.3 Mb. Depending on the species, 21,403–27,365 gene models were predicted. Using orthologous group analysis, single-copy and species-specific genes were identified. Primers and probes were designed targeting two species-specific genes in each species. The assays detected as low as 12 pg of DNA from the target species, or as few as five nematodes, with a Cq of 31 cycles or less. Our study provides genome data for two additional D. dipsaci isolates and two D. weischeri isolates, and four new and validated molecular assays to be used for rapid detection and identification of the two species.

ObjectivesOsteoarthritis is a leading cause of immobility and joint replacement, two strong risk factors for venous thromboembolism (VTE). We aimed to examine the relation of knee, hip and hand osteoarthritis to the risk of VTE and investigate joint replacement as a potential mediator.MethodsWe conducted three cohort studies using data from The Health Improvement Network. Up to five individuals without osteoarthritis were matched to each case of incident knee (n=20 696), hip (n=10 411) or hand (n=6329) osteoarthritis by age, sex, entry time and body mass index. We examined the relation of osteoarthritis to VTE (pulmonary embolism and deep vein thrombosis) using a multivariable Cox proportional hazard model.ResultsVTE developed in 327 individuals with knee osteoarthritis and 951 individuals without osteoarthritis (2.7 vs 2.0 per 1000 person-years), with multivariable-adjusted HR being 1.38 (95% CI 1.23 to 1.56). The indirect effect (HR) of knee osteoarthritis on VTE through knee replacement was 1.07 (95% CI 1.01 to 1.15), explaining 24.8% of its total effect on VTE. Risk of VTE was higher in hip osteoarthritis than non-osteoarthritis (3.3 vs 1.8 per 1000 person-years; multivariable-adjusted HR=1.83, 95% CI 1.56 to 2.13). The indirect effect through hip replacement yielded an HR of 1.14 (95% CI 1.04 to 1.25), explaining 28.1% of the total effect. No statistically significant difference in VTE risk was observed between hand osteoarthritis and non-osteoarthritis (1.5 vs 1.6 per 1000 person-years; multivariable-adjusted HR=0.88, 95% CI 0.67 to 1.16).ConclusionOur large population-based cohort study provides the first evidence that knee or hip osteoarthritis, but not hand osteoarthritis, was associated with an increased risk of VTE, and such an association was partially mediated through knee or hip replacement.

BackgroundLongitudinal evidence on change of serum urate level with mortality risk is limited as prior studies have a measurement of serum urate at a single time point. Further, the combined effect of serum urate and systemic inflammation on mortality is unknown.MethodsWe conducted a prospective cohort study of 152,358 participants (122,045 men and 30,313 women) with repeated measurements of serum urate in 2006, 2008, 2010, and 2012 (107,751 participants had all four measurements of serum urate). We used the Cox proportional hazard model to examine the association between cumulative average and changes in serum urate with mortality. The combined effect of serum urate and systemic inflammation was determined by testing the interaction of serum urate and high-sensitive C-reactive protein (hs-CRP) in relation to mortality risk.ResultsDuring a median follow-up of 8.7 (interquartile range 6.3–9.2) years, we identified 7564 all-cause deaths, 1763 CVD deaths, 1706 cancer deaths, and 1572 other deaths. We observed U-shaped relationships of cumulative average serum urate with all-cause mortality, cardiovascular mortality, and other mortalities. Compared with participants with stable serum urate, those with greater increases in serum urate had a 1.7-fold elevated mortality (hazard ratio (HR) = 1.66, 95% confidence interval (CI) = 1.49–1.84), and those with decreased serum urate had a 2-fold elevated mortality risk (HR = 2.14, 95% CI 1.93–2.37). Participants with both hyperuricemia and hs-CRP had 1.6 times higher mortality, compared with those with low serum urate and hs-CRP levels (HR = 1.56, 95% CI 1.37–1.76).ConclusionsWe observed a U-shaped relationship of long-term cumulative average serum urate with all-cause mortality, cardiovascular mortality, and other mortalities. Compared with participants with relatively stable serum urate levels, a greater increase or decrease in serum urate was associated with elevated mortality. Participants with both hyperuricemia and high systemic inflammation had the greatest mortality risk compared with those with low serum urate and low hs-CRP levels.

Background: Relationships between sleep duration, chronotype, insomnia, and lung cancer risk have not been comprehensively examined. Interrelations between sleep traits on the risk of lung cancer have not been assessed. We aimed to examine sleep traits with lung cancer risk. Methods: Participants were recruited between 2006 and 2010 and followed through November 30, 2020. We included 382,966 participants (3,664 incident lung cancer) in analysis. Cox proportional hazards models estimated HRs and 95% confidence intervals (CI) for associations between sleep duration, chronotype, and insomnia symptoms and lung cancer risk. Joint effects analyses were examined between sleep duration and three traits (chronotype, insomnia, and daytime napping). Nonlinear associations between sleep duration and lung cancer risk were assessed in restricted cubic spline analysis. Results: Longer sleep (>8 hours) was positively associated with lung cancer risk compared with normal sleep duration (7–8 hours; HR = 1.22; 95% CI, 1.10–1.36). Frequent insomnia symptoms increased the risk of lung cancer compared with never/rarely experiencing symptoms (HR = 1.16; 95% CI, 1.05–1.28). Joint effects between sleep duration and chronotype, and sleep duration and insomnia symptoms were observed. In analysis excluding participants reporting shift work at baseline, evening chronotypes (“slight,” “definite”) were at a greater risk of lung cancer compared with definite morning chronotype (HR = 1.17; 95% CI, 1.06–1.28 and HR = 1.37; 95% CI, 1.21–1.54, respectively). Conclusions: Sleep traits such as long sleep duration, frequent insomnia symptoms, and definite evening chronotype may be risk factors for lung cancer. Joint effects should be further investigated. Impact: Sleep traits may be risk factors of lung cancer.

Surveillance is a critical component of any dengue prevention and control program. There is an increasing effort to use drones in mosquito control surveillance. Due to the novelty of drones, data are scarce on the impact and acceptance of their use in the communities to collect health-related data. The use of drones raises concerns about the protection of human privacy. Here, we show how willingness to be trained and acceptance of drone use in tech-savvy communities can help further discussions in mosquito surveillance. A cross-sectional study was conducted in Malaysia, Mexico, and Turkey to assess knowledge of diseases caused by Aedes mosquitoes, perceptions about drone use for data collection, and acceptance of drones for Aedes mosquito surveillance around homes. Compared with people living in Turkey, Mexicans had 14.3 (p 0.0001) times higher odds and Malaysians had 4.0 (p = 0.7030) times the odds of being willing to download a mosquito surveillance app. Compared to urban dwellers, rural dwellers had 1.56 times the odds of being willing to be trained. There is widespread community support for drone use in mosquito surveillance and this community buy-in suggests a potential for success in mosquito surveillance using drones. A successful surveillance and community engagement system may be used to monitor a variety of mosquito spp. Future research should include qualitative interview data to add context to these findings.

The COVID-19 pandemic has increased utilization of educational technology for surgical education. Our aim was to determine attitudes and behaviors of surgical education champions towards virtual educational platforms and learner engagement.An electronic survey was distributed to all Association of Surgical Education members addressing i) methods of engagement in virtual learning ii) ways to improve engagement and iii) what influences engagement. Stratified analysis was used to evaluate differences in responses by age, gender, level of training and specialty.154 ASE members completed the survey (13% response rate). 88% respondents accessed virtual learning events at home. Most (87%) had joined a virtual learning event and then participated in another activity. 1 in 5 who did this did so "always" or "often". Female respondents were more likely than males to join audio and then participate in another activity (62.3% v 37.7%, p = 0.04).Virtual platforms do not automatically translate into increased learner engagement. Careful design of educational strategies is essential to increase and maintain learner engagement when utilizing virtual surgical education.

Resume Le syndrome de Binder est un syndrome malformatif rare dont la definition est clinique. L’etude scanographique d’une patiente presentant ce morphotype retrouvait un aspect de subduction de l’articulation palato-premaxillaire en coupe sagittale. L’objectif de cette etude etait d’analyser cette articulation dans une population temoin non atteinte du syndrome de Binder. Materiel et Methodes Nous avons selectionne retrospectivement 50 patients adultes caucasiens ayant un scanner sinusien realise entre 2013 et 2016 et presentant un angle nasolabial normal avec une bonne visualisation de l’articulation palato-premaxillaire sur une seule coupe sagittale. Apres analyse concertee de trois observateurs, les patients ont ete classes en deux groupes (A et S), selon qu’ils presentaient un aspect d’« affrontement » ou de « subduction » entre palais primaire et secondaire. Parallelement a l’analyse subjective des observateurs, les mesures suivantes ont ete comparees : l’angle palato-premaxillaire posterieur A1, l’angle palato-premaxillaire superieur A2, le debord « d » du premaxillaire au-dessus du palais secondaire. Resultats Cinquante patients ont ete inclus : 43 dans le groupe A et 7 dans le groupe S. L’angle A1 etait significativement different entre les groupes (111,95 ± 10,22° groupe A, versus 130,53 ± 10,0° groupe S, p = 0,0015). On ne retrouvait pas de difference significative pour les valeurs A2 et d entre les deux groupes. Conclusion Deux formes d’articulations palato-premaxillaires, par affrontement ou subduction, ont ete decrites dans la population etudiee. L’affrontement est la presentation la plus frequente. La subduction palato-premaxillaire ne permet pas a elle-seule de caracteriser le syndrome de Binder.

6-Thiopurine (6TP) is a potent cytotoxic agent that is a clinically prescribed anti-metabolite employed in the treatment of numerous blood cancers since 1952. However, its reported severe toxicities limit its general usage in the clinic. We previously have undertaken investigations into identifying the mode of toxicity for 6TP, and have found that the oxidative metabolites of 6TP, specifically 6-thiouric acid (6TU), is responsible for the in vitro inhibition of UDP-glucose dehydrogenase (UDPGDH) in a UV-vis method. In this method, inhibition was quantified through the quantification of NADH production, however, purines absorb at the same wavelength and thereby can interfere with the NADH detection. Herein, we report a HPLC method that allows for direct quantification of UDP-glucuronic acid, product from UDPGDH, for the assessment of inhibition towards UDPGDH with no interference from purines. In this method it was revealed that 6TP possesses a greater inhibitory properties than previously observed; 111 vs. 288 μM. Building upon the data collected from a previously performed rat hepatocyte study, which correlated our in vitro to in vivo inhibition theories about UDPGDH, we have developed a bio-mimic in vitro assay to aid in the inhibitory assessment of 6TP and analogs. In our efforts to expand the use of 6TP, and analogs constructed, our laboratory has undertaken a screening campaign to identify small molecule potentiators that work in synergy with 6TP in other types of cancers. Three chalcone-based compounds have been discovered through our total synthesis campaign of uvaretin, and it has been found that 11c has strong synergism with 6TP in the pancreatic cancer cell line MIA PaCa-2. Through the work presented herein, we reveal new methods to assess toxicity of 6TP and future analogs and new small molecules that work in synergy to expand the therapeutic applications of this neglected cytotoxic agent.

Hai Phong seaport (HPP) is the 2nd largest in Vietnam and the largest in the North. This port system is under planning to handle ships up to 50,000 (full load) and 132,000 DWT (under load). There are 3 main terminal zones: Cam river terminals, Dinh Vu terminals, Lach Huyen terminals. They have built since 1874, 1964, 1994, 2007, 2010, 2012 and 2018 on soft soil. There is an increase in cargo throughput, quantity, type and size of the sea fleet thought Hai Phong fairways. This has profoundly affected the ports’ infrastructure and equipment. HPP have relatively sufficient characteristics of evaluation and maintenance in Vietnam. The paper presents these studies and show some suitable solutions to improve life service and capacity of HPP.

Background Social support is a well-known protective factor against depressive symptoms and substance use problems, but very few studies have examined its protective effects among residents of permanent supportive housing (PSH), a housing program for people with a history of chronic homelessness. We utilized unconditional latent growth curve models (LGCMs) and parallel process growth models to describe univariate trajectories of social support, depressive symptoms, and substance use problems and to examine their longitudinal associations in a large sample of adults residing in PSH. Methods Participants were 653 adult PSH residents in North Texas (56% female; 57% Black; mean age: 51 years) who participated in a monthly health coaching program from 2014 to 2017. Their health behaviors were assessed at baseline and tracked every six months at three follow-up visits. Results Unconditional LGCMs indicated that over time, social support increased, whereas depressive symptoms and substance use problems decreased. However, their rates of change slowed over time. Further, in parallel process growth models, we found that at baseline, individuals with greater social support tended to have less severe depressive symptoms and substance use problems (coefficients: − 0.67, p Conclusions This study suggests that plausibly, increases in social support, though slowing over time, still positively impact depressive symptoms and substance use problems among PSH residents. Future PSH programs could emphasize social support as an early component as it may contribute to clients’ overall health.

Surgical treatment of spontaneous cerebrospinal fluid (CSF) leak is now performed by ENT surgeons, endonasal endoscopy being preferred to craniotomy as less invasive. However, it is often the symptom of underlying idiopathic intracranial hypertension, which lies outside the traditional sphere of ENT competence. Surgery is a necessary step, but should not obscure the need to treat the underlying pathology. This treatment is complex, and requires multidisciplinary team-work between otorhinolaryngologist, ophthalmologist, neurologist, neurosurgeon, radiologist, dietician, endocrinologist and psychotherapist. The present update details this multidisciplinary management to which the ENT surgeons must be attentive before and after spontaneous CSF leak repair.

Arboviruses such as Chikungunya (CHIKV), Dengue (DENV), and Zika virus (ZIKV) have emerged as a significant public health concern in Mexico. The existing literature lacks evidence regarding the dispersion of arboviruses, thereby limiting public health policy&rsquo, s ability to integrate the diagnosis, management, and prevention. This study seeks to reveal the clinical symptoms of CHIK, DENV, and ZIKV by age group, region, sex, and time across Mexico. The confirmed cases of CHIKV, DENV, and ZIKV were compiled from January 2012 to March 2020. Demographic characteristics analyzed significant clinical symptoms of confirmed cases. Multinomial logistic regression was used to assess the association between clinical symptoms and geographical regions. Females and individuals aged 15 and older had higher rates of reported significant symptoms across all three arboviruses. DENV showed a temporal variation of symptoms by regions 3 and 5, whereas ZIKV presented temporal variables in regions 2 and 4. This study revealed unique and overlapping symptoms between CHIKV, DENV, and ZIKV. However, the differentiation of CHIKV, DENV, and ZIKV is difficult, and diagnostic facilities are not available in rural areas. There is a need for adequately trained healthcare staff alongside well-equipped lab facilities, including hematological tests and imaging facilities.

Objectives To assess the efficacy of several repurposed drugs to prevent hospitalisation or death in patients aged 65 or more with recent symptomatic SARS-CoV-2 infection (COVID-19) and no criteria for hospitalisation. Trial design Phase III, multi-arm (5) and multi-stage (MAMS), randomized, open-label controlled superiority trial. Participants will be randomly allocated 1:1:1:1:1 to the following strategies: Arm 1: Control arm Arms 2 to 5: Experimental treatment arms Planned interim analyses will be conducted at regular intervals. Their results will be reviewed by an Independent Data and Safety Monitoring Board. Experimental arms may be terminated for futility, efficacy or toxicity before the end of the trial. New experimental arms may be added if new evidence suggests that other treatments should be tested. A feasibility and acceptability substudy as well as an immunological substudy will be conducted alongside the trial. Participants Inclusion criteria are: 65-year-old or more; Positive test for SARS-CoV-2 on a nasopharyngeal swab; Symptoms onset within 3 days before diagnosis; No hospitalisation criteria; Signed informed consent; Health insurance. Exclusion criteria are: Inability to make an informed decision to participate (e.g.: dementia, guardianship); Rockwood Clinical Frailty Scale ≥7; Long QT syndrome; QTc interval > 500 ms; Heart rate 5.5 mmol/L or The trial is being conducted in France in the Bordeaux, Corse, Dijon, Nancy, Paris and Toulouse areas as well as in the Grand Duchy of Luxembourg. Participants are recruited either at home, nursing homes, general practices, primary care centres or hospital outpatient consultations. Intervention and comparator The four experimental treatments planned in protocol version 1.2 (April 8th, 2020) are: (1) Hydroxychloroquine 200 mg, 2 tablets BID on day 0, 2 tablets QD from day 1 to 9; (2) Imatinib 400 mg, 1 tablet QD from day 0 to 9; (3) Favipiravir 200 mg, 12 tablets BID on day 0, 6 tablets BID from day 1 to 9; (4) Telmisartan 20 mg, 1 tablet QD from day 0 to 9. The comparator is a complex of vitamins and trace elements (AZINC Forme et Vitalité®), 1 capsule BID for 10 days, for which there is no reason to believe that they are active on the virus. In protocol version 1.2 (April 8th, 2020): People in the control arm will receive a combination of vitamins and trace elements; people in the experimental arms will receive hydroxychloroquine, or favipiravir, or imatinib, or telmisartan. Main outcome The primary outcome is the proportion of participants with an incidence of hospitalisation and/or death between inclusion and day 14 in each arm. Randomisation Participants are randomized in a 1:1:1:1:1 ratio to each arm using a web-based randomisation tool. Participants not treated with an ARB or ACEI prior to enrolment are randomized to receive the comparator or one of the four experimental drugs. Participants already treated with an ARB or ACEI are randomized to receive the comparator or one of the experimental drugs except telmisartan (i.e.: hydroxychloroquine, imatinib, or favipiravir). Randomisation is stratified on ACEI or ARBs treatment at inclusion and on the type of residence (personal home vs. nursing home). Blinding (masking) This is an open-label trial. Participants, caregivers, investigators and statisticians are not blinded to group assignment. Numbers to be randomised (sample size) A total of 1057 participants will be enrolled if all arms are maintained until the final analysis and no additional arm is added. Three successive futility interim analyses are planned, when the number of participants reaches 30, 60 and 102 in the control arm. Two efficacy analyses (interim n°3 and final) will be performed successively. Trial Status This describes the Version 1.2 (April 8th, 2020) of the COVERAGE protocol that was approved by the French regulatory authority and ethics committee. The trial was opened for enrolment on April 15th, 2020 in the Nouvelle Aquitaine region (South-West France). Given the current decline of the COVID-19 pandemic in France and its unforeseeable dynamic in the coming months, new trial sites in 5 other French regions and in Luxembourg are currently being opened. A revised version of the protocol was submitted to the regulatory authority and ethics committee on June 15th, 2020. It contains the following amendments: (i) Inclusion criteria: age ≥65 replaced by age ≥60; time since first symptoms <3 days replaced by time since first symptoms <5 days; (ii) Withdrawal of the hydroxychloroquine arm (due to external data); (iii) increase in the number of trial sites. Trial registration The trial was registered on Clinical Trials.gov on April 22nd, 2020 (Identifier: NCT04356495): and on EudraCT on April 10th, 2020 (Identifier: 2020-001435-27). Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

International audience; The difficulty of correcting nasal septum deformities using the classical Killian or Cottle techniques or derivatives has led in recent years to new suggestions such as extracorporeal septoplasty or various apposition grafts to counteract refractory deformity of the quadrangular cartilage. Naturally occurring septal deformities result from conflicts in growth between the quadrangular cartilage, perpendicular ethmoidal plate and vomer, which each have their own different evo-devo origin. Septoplasty by disarticulation consistently restores a level septum by completely resolving the growth conflicts. Conserving the quadrangular cartilage is essential for the stability of the nasal pyramid on condition that 1) the lateral flare of the superior edge of both the component septolateral cartilages that suspend it at the roof of the piriform orifice and 2) the height of its anterior edge are respected. The anterior edge is always high enough (except in case of fracture or malformation to project the retrolobular nasal dorsum in proportion to the height of the alar cartilage when it is repositioned on its natural premaxillary base.

In the Internet of Things (IoT) era, the capacity-limited Internet and uncontrollable service delays for various new applications, such as video streaming analysis and augmented reality, are challenges. Cloud computing systems, also known as a solution that offloads energy-consuming computation of IoT applications to a cloud server, cannot meet the delay-sensitive and context-aware service requirements. To address this issue, an edge computing system provides timely and context-aware services by bringing the computations and storage closer to the user. The dynamic flow of requests that can be efficiently processed is a significant challenge for edge and cloud computing systems. To improve the performance of IoT systems, the mobile edge orchestrator (MEO), which is an application placement controller, was designed by integrating end mobile devices with edge and cloud computing systems. In this paper, we propose a flexible computation offloading method in a fuzzy-based MEO for IoT applications in order to improve the efficiency in computational resource management. Considering the network, computation resources, and task requirements, a fuzzy-based MEO allows edge workload orchestration actions to decide whether to offload a mobile user to local edge, neighboring edge, or cloud servers. Additionally, increasing packet sizes will affect the failed-task ratio when the number of mobile devices increases. To reduce failed tasks because of transmission collisions and to improve service times for time-critical tasks, we define a new input crisp value, and a new output decision for a fuzzy-based MEO. Using the EdgeCloudSim simulator, we evaluate our proposal with four benchmark algorithms in augmented reality, healthcare, compute-intensive, and infotainment applications. Simulation results show that our proposal provides better results in terms of WLAN delay, service times, the number of failed tasks, and VM utilization.