Suppurative thyroiditis, a sign of branchiogenic fistula? Lesson based on a case report.

Branchiogenic fistulas are congenital alterations that affect the cervical compartments. Those of the fourth branchial cleft are rarest and can begin late with very serious complications. The suppurative thyroiditis can be a complication of these alterations. We describe a case of 3-year-old girl with high fever, left cervical swelling and increased inflammation indices. The neck ultrasound showed an abscess of the left thyroid lobe and a fluid mass with aerial content in laterocervical region. On MRI, the fluid mass extended from the left piriform sinus to the mediastinum. Fluoroscopy also highlighted a fistolose trait that extended from the left side wall of the esophagus, anteriorly towards the trachea. Treatment of these pathologies must be early and a late diagnosis can put patients' lives at risk.

Autologous neutralizing antibody responses after antiretroviral therapy in acute and early HIV-1.

BACKGROUND: Early antiretroviral therapy initiation (ARTi) in HIV-1 restricts reservoir size and diversity while preserving immune function, potentially improving opportunities for immunotherapeutic cure strategies. For antibody-based cure approaches, the development of autologous neutralizing antibodies (anAb) after acute/early ARTi is relevant, but poorly understood. METHODS: We characterize antibody responses in a cohort of 23 participants following ARTi in acute HIV (<60 days after infection) and early HIV (60-128 days after infection). RESULTS: Plasma virus sequences at the time of ARTi revealed evidence of escape from anAbs after early, but not acute, ARTi. HIV-1 Envs representing the transmitted/founder virus(es) (acute ARTi) or escape variants (early ARTi) were tested for sensitivity to longitudinal plasma IgG. After acute ARTi, no anAb responses developed over months to years of suppressive ART. In two of the three acute ARTi participants who experienced viremia after ARTi, however, anAbs arose shortly thereafter. After early ARTi, anAbs targeting those early variants developed between 12 and 42 weeks of ART and continued to increase in breadth and potency thereafter. CONCLUSIONS: Results indicate a threshold of virus replication (~60 days) required to induce anAbs, after which they continue to expand on suppressive ART to better target the range of reservoir variants. TRIAL REGISTRATION: NCT02656511FUNDING. National Institutes of Health grants U01AI169767; R01AI162646; UM1AI164570; UM1AI164560; U19AI096109; K23GM112526; T32AI118684, P30-AI-045008, P30 AI027763, R24 AI067039. Gilead Sciences grant INUS2361354; Viiv healthcare grant A126326.

B3GALT6 promotes dormant breast cancer cell survival and recurrence by enabling heparan sulfate-mediated FGF signaling.

Breast cancer mortality results from incurable recurrences thought to be seeded by dormant, therapy-refractory residual tumor cells (RTCs). Understanding the mechanisms enabling RTC survival is therefore essential for improving patient outcomes. Here, we derive a dormancy-associated RTC signature that mirrors the transcriptional response to neoadjuvant therapy in patients and is enriched for extracellular matrix-related pathways. In vivo CRISPR-Cas9 screening of dormancy-associated candidate genes identifies the galactosyltransferase B3GALT6 as a functional regulator of RTC fitness. B3GALT6 is required for glycosaminoglycan (GAG) linkage to proteins to generate proteoglycans, and its germline loss of function in patients causes skeletal dysplasias. We find that B3GALT6-mediated biosynthesis of heparan sulfate GAGs predicts poor patient outcomes and promotes tumor recurrence by enhancing dormant RTC survival in multiple contexts, and does so via a B3GALT6-heparan sulfate/HS6ST1-heparan 6-O-sulfation/FGF1-FGFR2 signaling axis. These findings implicate B3GALT6 in cancer and nominate FGFR2 inhibition as a promising approach to eradicate dormant RTCs and prevent recurrence.

Adaptation of a transmitted/founder simian-human immunodeficiency virus for enhanced replication in rhesus macaques.

Transmitted/founder (TF) simian-human immunodeficiency viruses (SHIVs) express HIV-1 envelopes modified at position 375 to efficiently infect rhesus macaques while preserving authentic HIV-1 Env biology. SHIV.C.CH505 is an extensively characterized virus encoding the TF HIV-1 Env CH505 mutated at position 375 shown to recapitulate key features of HIV-1 immunobiology, including CCR5-tropism, a tier 2 neutralization profile, reproducible early viral kinetics, and authentic immune responses. SHIV.C.CH505 is used frequently in nonhuman primate studies of HIV, but viral loads after months of infection are variable and typically lower than those in people living with HIV. We hypothesized that additional mutations besides Δ375 might further enhance virus fitness without compromising essential components of CH505 Env biology. From sequence analysis of SHIV.C.CH505-infected macaques across multiple experiments, we identified a signature of envelope mutations associated with higher viremia. We then used short-term in vivo mutational selection and competition to identify a minimally adapted SHIV.C.CH505 with just five amino acid changes that substantially improve virus replication fitness in macaques. Next, we validated the performance of the adapted SHIV in vitro and in vivo and identified the mechanistic contributions of selected mutations. In vitro, the adapted SHIV shows improved virus entry, enhanced replication on primary rhesus cells, and preserved neutralization profiles. In vivo, the minimally adapted virus rapidly outcompetes the parental SHIV with an estimated growth advantage of 0.14 days-1 and persists through suppressive antiretroviral therapy to rebound at treatment interruption. Here, we report the successful generation of a well-characterized, minimally adapted virus, termed SHIV.C.CH505.v2, with enhanced replication fitness and preserved native Env properties that can serve as a new reagent for NHP studies of HIV-1 transmission, pathogenesis, and cure.

Collective excitability in highly diluted random networks of oscillators.

We report on collective excitable events in a highly diluted random network of non-excitable nodes. Excitability arises thanks to a self-sustained local adaptation mechanism that drives the system on a slow timescale across a hysteretic phase transition involving states with different degrees of synchronization. These phenomena have been investigated for the Kuramoto model with bimodal distribution of the natural frequencies and for the Kuramoto model with inertia and a unimodal frequency distribution. We consider global and partial stimulation protocols and characterize the system response for different levels of dilution. We compare the results with those obtained in the fully coupled case showing that such collective phenomena are remarkably robust against network diluteness.

A rapid, specific, extraction-less, and cost-effective RT-LAMP test for the detection of SARS-CoV-2 in clinical specimens.

In 2019 a newly identified coronavirus, designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly from the epicenter in Wuhan (China) to more than 150 countries around the world, causing the Coronavirus disease 2019 (COVID-19) pandemic. In this study, we describe an extraction-less method based on reverse transcriptase loop-mediated isothermal amplification (RT-LAMP) intended for the rapid qualitative detection of nucleic acid from SARS-CoV-2 in upper respiratory specimens, including oropharyngeal and nasopharyngeal swabs, anterior nasal and mid-turbinate nasal swabs, nasopharyngeal washes/aspirates or nasal aspirates as well as bronchoalveolar lavage (BAL) from individuals suspected of COVID-19 by their healthcare provider. The assay's performance was evaluated and compared to an RT quantitative PCR-based assay (FDA-approved). With high sensitivity, specificity, and bypassing the need for RNA extraction, the RT-LAMP Rapid Detection assay is a valuable and fast test for an accurate and rapid RNA detection of the SARS-CoV-2 virus and potentially other pathogens. Additionally, the versatility of this test allows its application in virtually every laboratory setting and remote location where access to expensive laboratory equipment is a limiting factor for testing during pandemic crises.

Measurement of Penrose Superradiance in a Photon Superfluid.

The superradiant amplification in the scattering from a rotating medium was first elucidated by Sir Roger Penrose over 50 years ago as a means by which particles could gain energy from rotating black holes. Despite this fundamental process being ubiquitous also in wave physics, it has only been observed once experimentally, in a water tank. Here, we measure this amplification for a nonlinear optics experiment in the superfluid regime. In particular, by focusing a weak optical beam carrying orbital angular momentum onto the core of a strong pump vortex beam, negative norm modes are generated and trapped inside the vortex core, allowing for amplification of a reflected beam. Our experiment demonstrates amplified reflection due to a novel form of nonlinear optical four-wave mixing, whose phase-relation coincides with the Zel'dovich-Misner condition for Penrose superradiance in our photon superfluid, and unveil the role played by negative frequency modes in the process.

Detection of antibodies against SARS-CoV-2 both in plasma pools for fractionation and in commercial intravenous immunoglobulins produced from plasma collected in Italy during the pandemic.

BACKGROUND: We investigated the presence of anti-SARS-CoV-2 antibodies in Italian plasma pools and intravenous immunoglobulins sent to our Institute (Italian National Institute of Health - Istituto Superiore di Sanità) in the context of the Official Control Authority Batch Release. The plasma pools were made up from donations collected in several different Italian regions from May 2017 to October 2020, i.e. in the pre-pandemic and pandemic periods. MATERIALS AND METHODS: All plasma pools were initially tested for the qualitative detection of anti-SARS-CoV-2 antibodies against the nucleocapsid protein using the Roche Elecsys® Anti-SARS-CoV-2 test kit. Plasma pools positive for these antibodies were further tested using the Roche Elecsys® Anti-SARS-CoV-2 S test kit for the quantitative detection of antibodies against SARS-CoV-2 spike receptor binding domain. All plasma pools showing reactivity to these antibodies were tested undiluted for the presence of SARS-CoV-2 RNA using the Grifols Procleix SARS-CoV-2 transcription-mediated amplification assay. Intravenous immunoglobulins were tested using both test kits to determine the presence of anti-SARS-CoV-2 antibodies. RESULTS: All plasma pools made up from donations collected in the pre-pandemic period were negative for anti-SARS-CoV-2 antibodies against the nucleocapsid protein. Of the plasma pools made up from donations collected from December 2018 to March 2020, only 1 pool out of 68 (1.4%), that was made up from donations from the Lombardy region, was reactive for these antibodies. Interestingly, 105 out of 174 (60.3%) of the plasma pools made up from donations collected from November 2018 to October 2020 showed the presence of these antibodies. All plasma pools positive for these antibodies were tested for antibodies against SARS-CoV-2 spike receptor binding domain and were confirmed positive. DISCUSSION: None of these plasma pools tested were reactive for SARS-CoV-2 RNA. In the case of intravenous immunoglobulins, 20 out of 25 (80%) batches showed the presence of both anti-SARS-CoV-2 antibodies, reflecting the concentration in the plasma pools used for their production.

Isolation and Characterization of Mouse Monoclonal Antibodies That Neutralize SARS-CoV-2 and Its Variants of Concern Alpha, Beta, Gamma and Delta by Binding Conformational Epitopes of Glycosylated RBD With High Potency.

Antibodies targeting Receptor Binding Domain (RBD) of SARS-CoV-2 have been suggested to account for the majority of neutralizing activity in COVID-19 convalescent sera and several neutralizing antibodies (nAbs) have been isolated, characterized and proposed as emergency therapeutics in the form of monoclonal antibodies (mAbs). However, SARS-CoV-2 variants are rapidly spreading worldwide from the sites of initial identification. The variants of concern (VOC) B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.167.2 (Delta) showed mutations in the SARS-CoV-2 spike protein potentially able to cause escape from nAb responses with a consequent reduction of efficacy of vaccines and mAbs-based therapy. We produced the recombinant RBD (rRBD) of SARS-CoV-2 spike glycoprotein from the Wuhan-Hu 1 reference sequence in a mammalian system, for mice immunization to isolate new mAbs with neutralizing activity. Here we describe four mAbs that were able to bind the rRBD in Enzyme-Linked Immunosorbent Assay and the transmembrane full-length spike protein expressed in HEK293T cells by flow cytometry assay. Moreover, the mAbs recognized the RBD in supernatants of SARS-CoV-2 infected VERO E6 cells by Western Blot under non-reducing condition or in supernatants of cells infected with lentivirus pseudotyped for spike protein, by immunoprecipitation assay. Three out of four mAbs lost their binding efficiency to completely N-deglycosylated rRBD and none was able to bind the same recombinant protein expressed in Escherichia coli, suggesting that the epitopes recognized by three mAbs are generated by the conformational structure of the glycosylated native protein. Of particular relevance, three mAbs were able to inhibit Wuhan SARS-CoV-2 infection of VERO E6 cells in a plaque-reduction neutralization test and the Wuhan SARS-CoV-2 as well as the Alpha, Beta, Gamma and Delta VOC in a pseudoviruses-based neutralization test. These mAbs represent important additional tools for diagnosis and therapy of COVID-19 and may contribute to the understanding of the functional structure of SARS-CoV-2 RBD.

Social media use to improve communication on children and adolescent's health: the role of the Italian Paediatric Society influencers.

BACKGROUND: Fake news on children's and adolescent health are spreading. Internet availability and decreasing costs of media devices are contributing to an easy access to technology by families. Public health organizations are working to contrast misinformation and promote scientific communication. In this context, a new form of communication is emerging social media influencers. Aim of this study is to evaluate the role of paediatric influencers (PI) in communicating information about children and adolescents' health. MATERIALS AND METHODS: A group of PI was enrolled from December 2019 to January 2020 by a scientific commission nominated by the Italian Paediatric Society (SIP). PI were asked to share Facebook messages from the official page of the SIP to their own network. Social media tools have been evaluated across 12 months, from July 28, 2019, to July 11, 2020. For the purposes of clarity, we schematically divided the study period as follows: the period of PIs activity (January 6, 2020, to July 11, 2020) and the period when PIs were not yet active (July 28, 2019, to January 4, 2020). Information on Facebook page (lifetime total likes, daily new likes, daily page engaged, daily total reach) and on published post (lifetime post total reach, lifetime post organic reach, lifetime engaged users) were evaluated. RESULTS: A significant increase in Facebook daily new likes, page engagement and total reach, as well as in lifetime post total and organic reach was evidenced. As for PI, they reported a positive experience in most cases. DISCUSSION: In the digital era, communication strategies are becoming more important, so that the scientific community has to be actively involved in social media communication. Our pilot study demonstrated that the recruitment of paediatric influencers has increased communication and interaction of the SIP Facebook page. CONCLUSION: Our study shows the potential role of influencers: spreading health messages via PI seems to be a successful strategy to promote correct communication about children's and adolescents' health.

Children and Adolescent's Perception of Media Device Use Consequences.

Media device (MD) use is increasing worldwide among children. Adolescents and young children spend a lot of time using MD, Internet, and social networks. The age of initial use is getting lower to 12 years old. The aim of this research is to study children's use and perception of MD. The Italian Paediatric Society (SIP) conducted a Survey on Italian children in collaboration with Skuola.net using an online questionnaire. A total of 10,000 questionnaires were completed. Children admitted they spend more than 3 h (41%), more than 2 h (29%), more than 1 h (21%) and less than 1 h (9%) daily. Problematic MD use has been found with children using MD before sleeping (38%), during school (24%), and at wake up in the morning (21%). Addiction was documented in 14% of adolescents. Among the reported consequences, low academic outcomes, and reduced concentration (24%), neck and back pain (12%), insomnia (10%), and mood disturbances (7%) were referred. Adolescents may have a low perception of the risks related to excessive MD. The duration of time spent using media devices is a main risk factor. In this context, parents should strongly discourage excessive MD use, mainly during school, at bedtime, and wake-up. Additionally, parents should be informed and start conversations with their children on the potential negative effects of prolonged MD use.

Development of a new, simple, rapid ultra-high-performance liquid chromatography (UHPLC) method for the quantification of 2-phenoxyethanol in vaccines for human use.

A new, simple and rapid method for the quantitative determination of the antimicrobial preservative 2-phenoxyethanol, based on reverse phase ultra-high-performance liquid chromatography has been developed. The validation was performed according the ICH Q2 guideline "Validation of Analytical Procedures". The desired chromatographic separation was achieved on a Waters Symmetry C18 (150 × 4.6 mm, 5 µm) column using an isocratic elution, with detection at 270 nm wavelength. The mobile phase consisted of acetonitrile/water (55:45, v/v), pumped at a flow rate of 1 mL/min. The calibration curve and the analytical procedure are linear (r2 = 0.999) from the concentration of 0.07 mg/mL to 1.1 mg/mL. The percent relative standard deviation for intra- and inter-day precision was <1%. The recovery of 2-phenoxyethanol in vaccines ranged between 96.5 and 100.60%. The limits of detection and quantitation were 1.3 × 10-4 and 2.7 × 10-4 mg/mL, respectively. The method was found to be robust by changing the column working temperature, the percentage of acetonitrile of the mobile phase and the flow rate. The validated method can be successfully and reliably used to quantify as well as to exclude presence of 2-phenoxyethanol preservative in marketed vaccines.

Spatiotemporal representation of long-delayed systems: An alternative approach.

Dynamical systems with long-delay feedback can exhibit complicated temporal phenomena, which once reorganized in a two-dimensional space are reminiscent of spatiotemporal behavior. In this framework, a normal forms description has been developed to reproduce the dynamics, and the opportunity to treat the corresponding variables as true space and time has since been established. However, recently, an alternative approach has been proposed [F. Marino and G. Giacomelli, Phys. Rev. E 98, 060201(R) (2018)2470-004510.1103/PhysRevE.98.060201] with a different interpretation of the variables involved, which better takes into account their physical character and allows for an easier determination of the normal forms. In this paper, we extend such idea and apply it to a number of paradigmatic examples, paving the way to a rethinking of the concept of spatiotemporal representation of long-delayed systems.

Emergent excitability in populations of nonexcitable units.

Population bursts in a large ensemble of coupled elements result from the interplay between the local excitable properties of the nodes and the global network topology. Here, collective excitability and self-sustained bursting oscillations are shown to spontaneously emerge in globally coupled populations of nonexcitable units subject to adaptive coupling. The ingredients to observe collective excitability are the coexistence of states with different degrees of synchronization joined to a global feedback acting, on a slow timescale, against the synchronization (desynchronization) of the oscillators. These regimes are illustrated for two paradigmatic classes of coupled rotators, namely, the Kuramoto model with and without inertia. For the bimodal Kuramoto model we analytically show that the macroscopic evolution originates from the existence of a critical manifold organizing the fast collective dynamics on a slow timescale. Our results provide evidence that adaptation can induce excitability by maintaining a network permanently out of equilibrium.

Facial masks in children: the position statement of the Italian pediatric society.

Facial masks may be one of the most cost-effective strategies to prevent the diffusion of COVID 19 infection. Nevertheless, fake news are spreading, alerting parents on dangerous side effects in children, such as hypercapnia, hypoxia, gut dysbiosis and immune system weakness. Aim of the Italian Pediatric Society statement is to face misconception towards the use of face masks and to spread scientific trustable information.

SCOR: A secure international informatics infrastructure to investigate COVID-19.

Global pandemics call for large and diverse healthcare data to study various risk factors, treatment options, and disease progression patterns. Despite the enormous efforts of many large data consortium initiatives, scientific community still lacks a secure and privacy-preserving infrastructure to support auditable data sharing and facilitate automated and legally compliant federated analysis on an international scale. Existing health informatics systems do not incorporate the latest progress in modern security and federated machine learning algorithms, which are poised to offer solutions. An international group of passionate researchers came together with a joint mission to solve the problem with our finest models and tools. The SCOR Consortium has developed a ready-to-deploy secure infrastructure using world-class privacy and security technologies to reconcile the privacy/utility conflicts. We hope our effort will make a change and accelerate research in future pandemics with broad and diverse samples on an international scale.

Association between antithrombin and mortality in patients with COVID-19. A possible link with obesity.

BACKGROUND AND AIMS: Despite anticoagulation, usually with heparin, mortality for thromboembolic events in COVID-19 remains high. Clinical efficacy of heparin is due to its interaction with antithrombin (AT) that may be decreased in COVID-19. Therefore, we correlated AT levels with outcomes of COVID-19. METHODS AND RESULTS: We recruited 49 consecutive patients hospitalized for COVID-19. AT levels were significantly lower in 16 non-survivors than in 33 survivors (72.2 ± 23.4 versus 94.6 ± 19.5%; p = 0.0010). A multivariate Cox regression analysis showed that low AT (levels below 80%) was a predictor of mortality (HR:3.97; 95%CI:1.38 to 11.43; p = 0.0103). BMI was the only variable that showed a significant difference between patients with low and those with normal AT levels (32.9 ± 7.9 versus 27.5 ± 5.9%; p = 0.0104). AT levels were significantly lower in obese patients than in subjects with normal weight or overweight (77.9 ± 26.9 versus 91.4 ± 26.9 versus 91.4 ± 17.1%; p = 0.025). An inverse correlation between AT levels and BMI was documented (r:-0.33; p = 0.0179). CONCLUSIONS: Our data first suggest that AT is strongly associated with mortality in COVID-19. In addition, AT may be the link between obesity and a poorer prognosis in patients with COVID-19. Other studies should confirm whether AT may become a prognostic marker and a therapeutic target in COVID-19.

The use of web analytics combined with other data streams for tailoring online vaccine safety information at global level: The Vaccine Safety Net's web analytics project.

The Vaccine Safety Net's Web Analytics Project (VSN-WAP) was launched in October 2017 to monitor the behavior of users visiting websites belonging to the VSN, a global network of websites providing science-based information on vaccine safety. Participating websites could provide web metrics in two ways: through a Google Analytics (GA) script, which automatically forwarded metrics to a central account and through manual input (MI) of a reduced subset of metrics (Sessions, Page Views, New Users, Bounce Rate, Views/Session and Average Session Duration), which were pooled with the metrics obtained through GA. Additional metrics were obtained from websites providing data through Google Analytics (Country, Age, Sex, Device). We report results from February 2018 to March 2019. In March 2019, 32 websites were participating in the project (21 through GA, 11 through MI). From February 2018 to March 2019 we recorded 22,471,535 sessions, with 38,307,349 page views. Sessions, New Users and Page views progressively increased, Views/Session, Bounce Rate and Average Session Duration remained stable. Most users were female (68%) and belonged to the 25-34 age range (37%), followed by 35-44 (22%) and 18-24 (19%). Fifty-four percent of users connected from a mobile device, 42% from a desktop and 4% from a tablet. Digital media monitoring techniques can provide insights on the characteristics of users with a specific interest in vaccines. These data can be exploited to improve the performance of websites providing information on vaccines to the general public.

SPHN/PHRT - MedCo in Action: Empowering the Swiss Molecular Tumor Board with Privacy-Preserving and Real-Time Patient Discovery.

MedCo is the first operational system that makes sensitive medical-data available for research in a simple, privacy-conscious and secure way. It enables a consortium of clinical sites to collectively protect their data and to securely share them with investigators, without single points of failure. In this short paper, we report on our ongoing effort for the operational deployment of MedCo within the context of the Swiss Personalized Health Network (SPHN) for the Swiss Molecular Tumor Board.