Geographic tongue clinical response in moderate-to-severe psoriatic patients undergoing secukinumab: a real-life, multicenter retrospective observational study.

Geographic tongue (GT), a form of inverse psoriasis, is frequently linked to plaque psoriasis. The objective of the study is to evaluate IL-17 blocker (secukinumab) effect on GT severity. This reallife, multicenter, retrospective observational pilot study evaluated patients with plaque psoriasis and concomitant GT that started in label treatment with secukinumab. Patients were evaluated twice (T0=baseline and T1=after 16 weeks) by a dentist and a dermatologist collecting data on cutaneous Psoriasis Area Severity Index (PASI) and oral statuses using Hume's classification of the Geographic Tongue Severity Index (GTASI). Twenty-nine psoriatic patients with GT treated with secukinumab were enrolled for the study. Seventeen patients display type I GT, 6 type II and 6 type III with an overall GTASI of 25.52±9.57 at the baseline (T0). No correlation was found between delta GTASI and delta PASI (r=-0.27, p=0.1551). GTASI decrement from T0 to T1 was statistically significant ([95%CI -26.64 to -19.56], t=-13.36, p<0.0001). Secukinumab may enter in GT therapeutic armamentarium as the first biologic IL-17 blocker in patients with concomitant moderate-to-severe plaque psoriasis.

Cardiometabolic index: a new tool for screening the metabolically obese normal weight phenotype.

PURPOSE: People with the metabolically obese normal weight (MONW) phenotype are considered as an extremely high-risk group for unfavorable health consequences, but they are frequently undetected due to deceptive body mass index (BMI) and complex assessment. This study aimed to explore the clinical usefulness of cardiometabolic index (CMI) in identifying MONW individuals. METHODS: This cross-sectional study involved a total of 47,683 normal-weight subjects aged ≥ 18 years. Participants underwent anthropometrics, routine biochemical tests, and questionnaires for a full evaluation of the metabolic profile. The odds ratio (OR) of CMI and MONW phenotype was determined by the Logistic regression models and the diagnostic accuracy of CMI was evaluated by the receiver operating characteristic (ROC) curve analysis. RESULTS: The prevalence of MONW phenotype was 11.0%. After multivariate adjustment, the ORs for MONW in the highest compared with the lowest quartile of CMI was 71.20 (95% CI 55.19-91.86), and 1-SD increment of CMI brought a 54% additional risk. In ROC analysis, compared with BMI and waist circumference, CMI showed superior performance for identifying MONW individuals with an AUC of 0.853 (95% CI 0.847-0.860) in men and 0.912 (95% CI 0.906-0.918) in women, respectively. Moreover, CMI exhibited the highest diagnostic accuracy in younger age groups (aged 18-34 for men; aged 18-34 and 35-44 for women), in which AUCs surpassed 0.9 in both sexes. CONCLUSIONS: CMI could be served as a valuable indicator to identify MONW phenotype of Chinese adults, particularly for young people.

Sleep disorders and vascular responsiveness in patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is the most common systemic autoimmune disease characterized by chronic systemic inflammation. Half of the deaths of patients with RA are due to cardiovascular diseases (CVD), considered to be 1.5 to -2.0-fold that in the general population. Patients with RA also experience poor sleep, which by itself is associated with endothelial dysfunction, CVD events and sudden death. Our aim was to study the mechanistic pathways and the correlations between sleep efficiency and vascular reactivity of patients with RA. METHODS AND RESULTS: A prospective study that evaluated quality of sleep using ACTi Graphs, vascular inflammation and endothelial function of 18 patients with RA. Inflammation was studied by levels of E-selectin, intercellular adhesion molecule 1 (ICAM-1) and NO in serum. Endothelial function was studied using the brachial artery plethysmography method. Eighteen RA patients (aged 57.56 ± 13.55 years; 16 women) with a long-standing active RA: Eight patients had impaired sleep efficiency and 10 had a good sleep efficiency. Those who had an impaired sleep had larger baseline diameters of the brachial artery (0.39 ± 0.08 cm vs. 0.32 ± 0.04 cm; P = 0.02). Negative correlations were found between baseline brachial artery diameter and sleep efficiency (P = 0.01), and with NO level (P = 0.04). Stepwise regression found that brachial artery diameter at baseline and NO level could predict sleep efficiency (r2  = 0.543, P = 0.01). CONCLUSION: Vascular reactivity could predict quality of sleep in patients with RA. Quality of sleep may serve as an independent CVD risk factor in patients with RA.

Artificial neural networks allow response prediction in squamous cell carcinoma of the scalp treated with radiotherapy.

BACKGROUND: Epithelial neoplasms of the scalp account for approximately 2% of all skin cancers and for about 10-20% of the tumours affecting the head and neck area. Radiotherapy is suggested for localized cutaneous squamous cell carcinomas (cSCC) without lymph node involvement, multiple or extensive lesions, for patients refusing surgery, for patients with a poor general medical status, as adjuvant for incompletely excised lesions and/or as a palliative treatment. To date, prognostic risk factors in scalp cSCC patients are poorly characterized. OBJECTIVE: To identify patterns of patients with higher risk of postradiotherapy recurrence. METHODS: A retrospective observational study was performed on scalp cSCC patients with histological diagnosis who underwent conventional radiotherapy (50-120 kV) (between 1996 and 2008, follow-up from 1 to 140 months, median 14 months). Out of the 79 enrolled patients, 22 (27.8%) had previously undergone a surgery. Two months after radiotherapy, 66 (83.5%) patients achieved a complete remission, 6 (7.6%) a partial remission, whereas 2 (2.5%) proved non-responsive to the treatment and 5 cases were lost to follow-up. Demographical and clinical data were preliminarily analysed with classical descriptive statistics and with principal component analysis. All data were then re-evaluated with a machine learning-based approach using a 4th generation artificial neural networks (ANNs)-based algorithm. RESULTS: Artificial neural networks analysis revealed four scalp cSCC profiles among radiotherapy responsive patients, not previously described: namely, (i) stage T2 cSCC type, aged 70-80 years; (ii) frontal cSCC type, aged <70 years; (iii) non-recurrent nodular or nodulo-ulcerated, stage T3 cSCC type, of the vertex and treated with >60 Grays (Gy); and (iv) flat, occipital, stage T1 cSCC type, treated with 50-59 Gy. The model uncovering these four predictive profiles displayed 85.7% sensitivity, 97.6% specificity and 91.7% overall accuracy. CONCLUSIONS: Patient profiling/phenotyping with machine learning may be a new, helpful method to stratify patients with scalp cSCCs who may benefit from a RT-treatment.

Photoadaptation to ultraviolet B TL01 in psoriatic patients.

BACKGROUND: In the biologic era, narrow-band ultraviolet B (NB-UVB) phototherapy still remains a valuable, effective, inexpensive, safe anti-psoriatic treatment. Patients can lose response to NB-UVB over time due to photoadaptation. This phenomenon is the tendency of the skin to respond to ultraviolet (UV) exposure by undergoing changes that may result in a decreased future response to an equivalent dose of radiation, thus leading to the need for an increased exposure during phototherapy course. AIM: To characterize and quantify the determinants of photoadaptation in NB-UVB treated psoriatic patients. METHODS: We enrolled 57 adult patients with moderate plaque psoriasis. Patients underwent 24 sessions of NB-UVB phototherapy delivered thrice a week. Dosing was started with 70% of the minimal erythema dose (MED) with percentage-based dose increments every two treatments. MED as well as change in the erythema and melanin index (MI) were measured at baseline and at the end of phototherapy course. Moreover, an adaptation factor (AF) was calculated for each patient. RESULTS: Adaptation factor was not influenced by both baseline MED and skin type. We found a weak correlation between higher cumulative dosages and the initial MED (Spearman's rho = 0.32, P = 0.0154) as well as with the mean initial MI (Spearman's rho = 0.25, P = 0.0624, statistically borderline). Clearance and mean number of treatments were correlated (Spearman's rho = 0.48, P < 0.001). CONCLUSION: Photoadaptation is a physiological skin response that negatively influences NB-UVB responsiveness and is not predictable by the baseline MED and skin type. Thus, starting with more aggressive protocols and increasing rapidly dosage progression to prevent AF may increase NB-UVB response.

Decrease in 14-3-3η protein levels is correlated with improvement in disease activity in patients with rheumatoid arthritis treated with Tofacitinib.

14-3-3η protein is a proinflammatory mediator that may represent a novel diagnostic and prognostic biomarker for rheumatoid arthritis (RA). We assessed the correlation between changes in serum 14-3-3η levels and changes in clinical disease activity measures in RA patients treated with Tofacitinib (TOF). Paired serum samples from 35 patients with RA were obtained at baseline and 5 months after the initiation of treatment with TOF. The levels of 14-3-3η were measured by JOINT stat 14-3-3η ELISA test kits (Augurex Life Sciences Corp.). The cut-off was defined as 0.19 ng/ml. 14-3-3η positivity was found in 57% of the patients at baseline and in 37% of the patients after 5 months of treatment. Mean ± SD baseline 14-3-3η levels [4.92 ± 8.86 ng/ml] were significantly higher (p < 0.005) than 14-3-3η levels following treatment [1.97 ± 4.59 ng/ml]. A statistically significant improvement (p < 0.001) of CDAI, SDAI, DAS4ESR and DAS4CRP was achieved after 5 month of treatment. Decrease in 14-3-3η protein levels was highly correlated with improvement in DAS4ESR (r = 0.50, p < 0.01), DAS4CRP (r = 0.46, p < 0.01) and ESR (r = 0.36, p = 0.03) and moderately correlated with improvement in CDAI (r = 0.32, p = 0.065) and SDAI (r = 0.33, p = 0.051). The correlation between decrease in 14-3-3η levels and improvement in DAS4ESR remained significant in a partial correlation analysis controlling for ESR (r = 0.39, p = 0.02). This study demonstrates that in RA patients who were treated with TOF, decrease in 14-3-3η levels is correlated with improvement in clinical disease activity parameters. The 14-3-3η protein may serve as an objective biomarker for monitoring of TOF therapy response.

Tuftsin-phosphorylcholine (TPC) equally effective to methylprednisolone in ameliorating lupus nephritis in a mice model.

The role of helminth treatment in autoimmune diseases is growing constantly. Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease with challenging treatment options. Tuftsin-phosphorylcholine (TPC) is a novel helminth-based compound that modulates the host immune network. This study was conducted to evaluate the potential value of TPC in ameliorating lupus nephritis in a murine model and specifically to compare the efficacy of TPC to the existing first-line therapy for SLE: corticosteroids (methylprednisolone). Lupus-prone NZBxW/F1 mice were treated with TPC (5 µg/mouse), methylprednisolone (MP; 5 mg/body weight) or phosphate-buffered saline (PBS) (control) three times per week once glomerulonephritis, defined as proteinuria of grade > 100 mg/dl, was established. Levels of anti-dsDNA autoantibodies were evaluated by enzyme-linked immunosorbent assay (ELISA), splenic cytokines were measured in vitro and the kidney microscopy was analysed following staining. TPC and MP treatments improved lupus nephritis significantly and prolonged survival in NZBxW/F1 mice. TPC-treated mice showed a significantly decreased level of proteinuria (P < 0·001) and anti-dsDNA antibodies (P < 0·001) compared to PBS-treated mice. Moreover, TPC and MP inhibited the production of the proinflammatory cytokines interferon IFN-γ, interleukin IL-1ß and IL-6 (P < 0·001) and enhanced expression of the anti-inflammatory cytokine IL-10 (P < 0·001). Finally, microscopy analysis of the kidneys demonstrated that TPC-treated mice maintained normal structure equally to MP-treated mice. These data indicate that the small molecule named TPC hinders lupus development in genetically lupus-prone mice equally to methylprednisolone in most of the cases. Hence, TCP may be employed as a therapeutic potential for lupus nephritis.

A critical appraisal of randomized controlled trials on intravenous phenytoin in convulsive status epilepticus.

Since the 1970s, intravenous (IV) phenytoin (PHT) has traditionally been used as second-stage treatment for convulsive status epilepticus (SE) after failure of benzodiazepines. The aim of this review was to critically assess the evidence supporting the use of IV PHT as treatment of convulsive SE in patients of any age. In particular, we critically appraised the results of randomized controlled trials (RCTs) evaluating IV PHT as treatment of convulsive SE. A systematic search of the literature was carried out to identify RCTs evaluating IV PHT as treatment of convulsive SE in patients of any age. Eight RCTs (544 patients allocated to IV PHT) were included. The included studies differed in almost every single characteristic considered. Six RCTs (472 patients) used IV PHT without demonstrating refractoriness of SE to benzodiazepines. Only two RCTs (72 patients) used IV PHT as second-line treatment for benzodiazepine-resistant convulsive SE. Overall, most evidence from RCTs supports the use of IV PHT immediately after IV diazepam, even if seizures have not recurred. The recommendation derived from RCTs supporting the use of IV PHT as second-line treatment in benzodiazepine-resistant convulsive SE is weak. This is emblematic of the lack of robust evidence from large RCTs to inform clinical practice on how to treat SE after failure of first-line drugs. IV PHT given immediately after first-line benzodiazepines could prolong their short antiepileptic effect and prevent seizure recurrence.

Monitoring public interest toward pertussis outbreaks: an extensive Google Trends-based analysis.

OBJECTIVES: Pertussis is a vaccine-preventable disease. Despite this, it remains a major health problem among children in developing countries and in recent years, has re-emerged and has led to considerable outbreaks. Pertussis surveillance is of paramount importance; however, classical monitoring approaches are plagued by some shortcomings, such as considerable time delay and potential underestimation/underreporting of cases. STUDY DESIGN: This study aims at investigating the possibility of using Google Trends (GT) as an instrument for tracking pertussis outbreaks to see if infodemiology and infoveillance approaches could overcome the previously mentioned issues because they are based on real-time monitoring and tracking of web-related activities. METHODS: In the present study, GT was mined from inception (01 January 2004) to 31 December 2015 in the different European countries. Pertussis was searched using the 'search topic' strategy. Pertussis-related GT figures were correlated with the number of pertussis cases and deaths retrieved from the European Centre for Disease prevention and Control database. RESULTS: At the European countries level, correlation between pertussis cases and GT-based search volumes was very large (ranging from 0.94 to 0.97) from 2004 to 2015. When examining each country, however, only a few reached the threshold of statistical significance. CONCLUSIONS: GT could be particularly useful in pertussis surveillance and control, provided that the algorithm is better adjusted and refined at the country level.

Anterior ST-elevation myocardial infarction induced by rituximab infusion: A case report and review of the literature.

WHAT IS KNOWN AND OBJECTIVES: Rituximab is a chimeric monoclonal anti-CD20 antibody approved for the treatment of some lymphoid malignancies as well as for autoimmune diseases including rheumatoid arthritis (RA), idiopathic thrombocytopenic purpura (ITP) and vasculitis. Generally, rituximab is well tolerated; nevertheless, some patients develop adverse effects including infusion reactions. Albeit rare, these reactions may in some cases be life-threatening conditions. Rituximab cardiovascular side effects include more common effects such as hypertension, oedema and rare cases of arrhythmias and myocardial infarction. CASE SUMMARY: In this article, we report a case of a 58-year-old man with a history of overlap syndrome including RA and limited scleroderma who was treated with rituximab and developed a dramatic ST-elevation myocardial infarction (STEMI) during the drug administration. WHAT IS NEW AND CONCLUSION: This report underlines previous published reports emphasizing the awareness of such an association. This communication also warrants the importance of screening for ischaemic heart disease in selected cases of patients treated with rituximab.

The history of tuberculosis: from the first historical records to the isolation of Koch's bacillus.

Tuberculosis (TB) is a contagious, infectious disease, due to Mycobacterium tuberculosis (MT) that has always been a permanent challenge over the course of human history, because of its severe social implications. It has been hypothesized that the genus Mycobacterium originated more than 150 million years ago. In the Middle Ages, scrofula, a disease affecting cervical lymph nodes, was described as a new clinical form of TB. The illness was known in England and France as "king's evil", and it was widely believed that persons affected could heal after a royal touch. In 1720, for the first time, the infectious origin of TB was conjectured by the English physician Benjamin Marten, while the first successful remedy against TB was the introduction of the sanatorium cure. The famous scientist Robert Koch was able to isolate the tubercle bacillus and presented this extraordinary result to the society of Physiology in Berlin on 24 March 1882. In the decades following this discovery, the Pirquet and Mantoux tuberculin skin tests, Albert Calmette and Camille Guérin BCG vaccine, Selman Waksman streptomycin and other anti-tuberculous drugs were developed.

Intraoperative non invasive intracranial pressure monitoring during pneumoperitoneum: a case report and a review of the published cases and case report series.

Non-invasive measurement of ICP (nICP) can be warranted in patients at risk for developing increased ICP during pneumoperitoneum (PP). Our aim was to assess available data on the application of nICP monitoring during these procedures and to present a patient assessed with an innovative combination of noninvasive tools. Literature review of nICP assessment during PP did not find any studies comparing different methods intraprocedurally and only few studies of any nICP monitoring were available: transcranial Doppler (TCD) studies used the pulsatility index (PI) as an estimator of ICP and failed to detect a significant ICP increase during PP, whereas two out of three optic nerve sheath diameter (ONSD) studies detected a statistically significant ICP increase. In the case study, we describe a 52 year old man with a high grade thalamic glioma who underwent urgent laparoscopic cholecystectomy. Considering the high intraoperative risk of developing intracranial hypertension, he was monitored through parallel ONSD ultrasound measurement and TCD derived formulae (flow velocity diastolic formula, FVdnICP, and PI). ONSD and FVdnICP methods indicated a significant ICP increase during PP, whereas PI was not significantly increased. Our experience, combined with the literature review, seems to suggest that PI might not detect ICP changes in this context, however we indicate a possible interest of nICP monitoring during PP by means of ONSD and of TCD derived FVdNICP, especially for patients at risk for increased ICP.

The old and the new: vaccine hesitancy in the era of the Web 2.0. Challenges and opportunities.

The phenomenon known as vaccine hesitancy (a term that includes the concepts of indecision, uncertainty, delay and reluctance) is complex, closely linked to social contexts, and has different determinants: historical period, geographical area, political situation, complacency, convenience and confidence in vaccines. The World Health Organization (WHO) recommends that vaccine hesitancy and any proxy of it should be constantly monitored. Given the growing importance and pervasiveness of information and communication technologies (ICTs), the new media could be exploited in order to track lay-people's perceptions of vaccination in real time, thereby enabling health-care workers to actively engage citizens and to plan ad hoc communication strategies. Analysis of so-called "sentiments" expressed through the new media (such as Twitter) and the real-time tracking of web-related activities enabled by Google Trends, combined with the administration of specific online "surveys" on well-defined themes to target groups (such as health-care workers), could constitute a "Fast data monitoring system" that yields a snapshot of perceptions of vaccination in a given place and at a specific time. This type of dashboard could be a strategic tool that enables public services to organize targeted communication actions aimed at containing vaccine hesitancy.

History and evolution of influenza control through vaccination: from the first monovalent vaccine to universal vaccines.

Influenza is a highly infectious airborne disease with an important epidemiological and societal burden; annual epidemics and pandemics have occurred since ancient times, causing tens of millions of deaths. A hundred years after this virus was first isolated, influenza vaccines are an important influenza prevention strategy and the preparations used display good safety and tolerability profiles. Innovative tools, such as recombinant technologies and intra-dermal devices, are currently being investigated in order to improve the immunological response. The recurring mutations of influenza strains has prompted the recent introduction of a quadrivalent inactivated vaccine. In the near future, scientific research will strive to produce a long-lasting universal vaccine containing an antigen that will offer protection against all influenza virus strains.

Agility training in young elite soccer players: promising results compared to change of direction drills.

The aim of this study was to compare the effect of two different training programmes - change of direction (COD) vs. agility (AG) - on straight sprint (SS), COD and AG test performances in young elite soccer players. Thirty-two soccer players (age: 14.5±0.9 years; height: 171.2±5.1 cm; body mass: 56.4±7.1 kg, body fat: 10.3±2.3%) participated in a short-term (6 weeks) training study. Players were randomly assigned to two experimental groups - training with change of direction drills (COD-G, n=11) or using agility training (AG-G, n= 11) - and to a control group (CON-G, n=10). All players completed the following tests before and after training: straight sprint (15m SS), 15 m agility run with (15m-AR-B) and without a ball (15m-AR), 5-0-5 agility test, reactive agility test (RAT), and RAT test with ball (RAT-B). A significant group effect was observed for all tests (p<0.001; η2=large). In 15m SS, COD-G and AG-G improved significantly (2.21; ES=0.57 and 2.18%; ES=0.89 respectively) more than CON-G (0.59%; ES=0.14). In the 15m-AR and 5-0-5 agility test, COD-G improved significantly more (5.41%; ES=1.15 and 3.41; ES=0.55 respectively) than AG-G (3.65%; ES=1.05 and 2.24; ES=0.35 respectively) and CON-G (1.62%; ES=0.96 and 0.97; ES=0.19 respectively). Improvements in RAT and RAT-B were larger (9.37%; ES=2.28 and 7.73%; ES=2.99 respectively) in RAT-G than the other groups. In conclusion, agility performance amongst young elite soccer could be improved using COD training. Nevertheless, including a conditioning programme for agility may allow a high level of athletic performance to be achieved.

An unusual cause of dysphagia: "DISHphagia".

Progressive dysphagia and dyspnoea presenting after major neck trauma can occasionally be secondary to post-traumatic inflammation and mass effect associated with a calcified osteophytic anterior longitudinal ligament, a frequent finding in diffuse idiopathic skeletal hyperostosis, though rarely enough to cause such symptoms. In these circumstances, surgical decompression may prove effective.

Cancer prevention: state of the art and future prospects.

Cancer imposes a heavy societal burden worldwide, in terms of both epidemiology and costs. The introduction of more sophisticated imaging and diagnostic techniques and advanced drugs that specifically target tumor cells is leading to increasingly expensive treatments, which may be affordable only for few patients. Prevention, and particularly primary prevention, is an effective way of addressing the challenging issue of cancer, since between a third and a half of cancers could be prevented on the basis of our current knowledge of risk factors. Moreover, prevention is cost-effective, its effects are not limited to high-risk subjects but extend to the entire population, and it is not dependent on socioeconomic status. Regulatory measures can have a broad impact, even on future generations; by empowering and educating subjects, promoting healthy behaviours and teaching self-care, they can trigger a virtuous cycle. In recent decades, oncology has shifted from being merely reactive to being proactive; this shift has led to the development of so-called "P4 medicine", where the 4 Ps stand for "preventive", "predictive", "personalized" and "participatory". Prevention programs are an important part of the effort to control cancer, as they are able to reduce both the incidence of cancer and mortality. For instance, screening for colorectal, breast and cervical cancer is reducing the burden of these common tumors. Anti-cancer vaccines, both prophylactic and therapeutic, constitute another important preventive tool. Although progress has been made in these areas, much remains to be done. With regard to screening programs, coverage could be increased by introducing new, more acceptable, less invasive tests, stratifying screening through correlation with anamnestic, clinical, radiological and genomic data (so-called "populationbased personalized cancer screening"), and exploiting new information and communication technologies, such as smartphone applications or personalized text messages (so-called "screening 2.0"). Advocacy and recommendations by physicians can also play a role, in that eligible subjects need to be able to discuss their doubts and their perceived psycho-social barriers. However, new screening initiatives should be implemented only after a careful health technology assessment has been performed within the framework of evidence-based medicine, organized screening programs have been strengthened and opportunistic or spontaneous programs have been limited.

Compounds with anti-influenza activity: present and future of strategies for the optimal treatment and management of influenza. Part II: Future compounds against influenza virus.

In the first part of this overview, we described the life cycle of the influenza virus and the pharmacological action of the currently available drugs. This second part provides an overview of the molecular mechanisms and targets of still-experimental drugs for the treatment and management of influenza. Briefly, we can distinguish between compounds with anti-influenza activity that target influenza virus proteins or genes, and molecules that target host components that are essential for viral replication and propagation. These latter compounds have been developed quite recently. Among the first group, we will focus especially on hemagglutinin, M2 channel and neuraminidase inhibitors. The second group of compounds may pave the way for personalized treatment and influenza management. Combination therapies are also discussed. In recent decades, few antiviral molecules against influenza virus infections have been available; this has conditioned their use during human and animal outbreaks. Indeed, during seasonal and pandemic outbreaks, antiviral drugs have usually been administered in mono-therapy and, sometimes, in an uncontrolled manner to farm animals. This has led to the emergence of viral strains displaying resistance, especially to compounds of the amantadane family. For this reason, it is particularly important to develop new antiviral drugs against influenza viruses. Indeed, although vaccination is the most powerful means of mitigating the effects of influenza epidemics, antiviral drugs can be very useful, particularly in delaying the spread of new pandemic viruses, thereby enabling manufacturers to prepare large quantities of pandemic vaccine. In addition, antiviral drugs are particularly valuable in complicated cases of influenza, especially in hospitalized patients. To write this overview, we mined various databases, including Embase, PubChem, DrugBank and Chemical Abstracts Service, and patent repositories.

Compounds with anti-influenza activity: present and future of strategies for the optimal treatment and management of influenza. Part I: Influenza life-cycle and currently available drugs.

Influenza is a contagious respiratory acute viral disease characterized by a short incubation period, high fever and respiratory and systemic symptoms. The burden of influenza is very heavy. Indeed, the World Health Organization (WHO) estimates that annual epidemics affect 5-15% of the world's population, causing up to 4-5 million severe cases and from 250,000 to 500,000 deaths. In order to design anti-influenza molecules and compounds, it is important to understand the complex replication cycle of the influenza virus. Replication is achieved through various stages. First, the virus must engage the sialic acid receptors present on the free surface of the cells of the respiratory tract. The virus can then enter the cells by different routes (clathrin-mediated endocytosis or CME, caveolae-dependent endocytosis or CDE, clathrin-caveolae-independent endocytosis, or macropinocytosis). CME is the most usual pathway; the virus is internalized into an endosomal compartment, from which it must emerge in order to release its nucleic acid into the cytosol. The ribonucleoprotein must then reach the nucleus in order to begin the process of translation of its genes and to transcribe and replicate its nucleic acid. Subsequently, the RNA segments, surrounded by the nucleoproteins, must migrate to the cell membrane in order to enable viral assembly. Finally, the virus must be freed to invade other cells of the respiratory tract. All this is achieved through a synchronized action of molecules that perform multiple enzymatic and catalytic reactions, currently known only in part, and for which many inhibitory or competitive molecules have been studied. Some of these studies have led to the development of drugs that have been approved, such as Amantadine, Rimantadine, Oseltamivir, Zanamivir, Peramivir, Laninamivir, Ribavirin and Arbidol. This review focuses on the influenza life-cycle and on the currently available drugs, while potential antiviral compounds for the prevention and treatment of influenza are considered in the subsequent review.

Markers of community outbreak and facility type for mitigation of COVID-19 in long-term care homes in Ontario, Canada: Insights and implications from a time-series analysis.

PURPOSE: The resident deaths among Long Term Care Home (LTCH) accounted for more than 65% of total deaths in the province of Ontario, Canada, during March 29 to June 3, 2020, yet not all LTCHs were severely affected. METHODS: We carried out a retrospective cohort study, with case control for questions for which data allowed, with LTCH COVID-19 databases obtained from Ontario's Ministry of Long Term Care. We performed a combined temporal and spatial data analysis of COVID-19 cases and deaths among LTCH residents, identified trends, contributing factors, and early markers of LTCH outbreak severity. RESULTS: Our analysis shows that for-profit LTCHs had higher death-to-bed ratio, also with an average rate of increase of death-to-bed ratio higher for for-profit homes than other types of management. We find from uni- and multi-variable analyses (linear and nonlinear) that staff infection has the strongest association with death-to-bed ratio from among the descriptor variables considered, reflecting the risk of the disease in the health region/community. We also identify a delay of up to 8 days between the trends in fatalities among individuals outside LTCHs and that of LTCH residents. We did find an association between policy change to single LTCH/staff and reduction in weekly LTCH resident death, albeit with an expected time delay of about 7-10 days. CONCLUSIONS: The association between the risk of COVID-19 in the health region and the deaths among LTCH residents, and the delay between fatality among individuals residing outside and inside LTCHs suggests that fatality in a health region could be a predictor of outbreak in LTCHs within the same health region.