Surgery- vs Radiation-Based Therapy for p16+/HPV-Related Oropharyngeal Cancers

Abstract

Purpose of Review

Oropharyngeal cancer (OPC) has traditionally been managed by radiotherapy (RT)-based approaches. Minimally invasive surgery [transoral robotic surgery (TORS)/transoral laser microsurgery (TLMS)] is gaining popularity in T1-T2 HPV+ OPC. However, there is lack of high level evidence to guide practice. We summarize ongoing research regarding outcomes and investigational strategies for TORS/TLM- and RT-based treatments for this disease.

Recent Findings

Literature published in 2012–2017 demonstrated comparable exemplary outcomes with TORS/TLM and IMRT for selected HPV+ T1-T2 OPC. However, many TORS/TLM-treated patients also require adjuvant treatment, which impacts quality of life. Emerging RT-based de-intensification trial data suggest promising results. Ongoing investigation include indications for postoperative (chemo-)radiotherapy following TORS/TLM- and optimal RT-based de-intensification strategies.

Summary

A contemporary literature review demonstrates equal efficacy for TORS/TLM and IMRT as primary treatment for selected HPV+ T1-T2 OPC. TORS/TLM is an attractive approach when the opportunity for single modality treatment is high.

https://ift.tt/2A4MOFz

Relations between epidermal barrier dysregulation and staphylococci-dominated microbiome dysbiosis in atopic dermatitis

Publication date: Available online 24 July 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Can Altunbulakli, Matthias Reiger, Avidan U. Neumann, Natalie Garzorz-Stark, Megan Fleming, Claudia Huelpuesch, Francesc Castro-Giner, Kilian Eyerich, Cezmi A. Akdis, Claudia Traidl-Hoffmann

https://ift.tt/2LhZ4Yu

Investigation of the mtDNA mutations in Syrian Families With Non-Syndromic Sensorineural Hearing Loss

Publication date: Available online 24 July 2018

Source: International Journal of Pediatric Otorhinolaryngology

Author(s): Faten Moassass, Bassel AL-Halabi, Mohamad Sayah Nweder, Walid AL-Achkar

Abstract

Objective

Hearing loss is a common sensory disorder, and at least 50% of cases are due to a genetic etiology. Several mitochondrial DNA mutations (mtDNA) have been reported to be associated with nonsyndromic hearing loss (NSHL) in different population. However, There is no previous available data about the frequency of mtDNA mutations as etiology for deafness in Syrian. The aim of present study is to investigate the incidence of common mt DNA mutations in our families with congenital hearing loss and not related to the ototoxicity or aminoglycosides.

Methods

A total of 50 deaf families were enrolled in the present study. Direct sequencing and PCR-RFLP methods were employed to detect seven mt DNA mutations, including A1555G, A3243G, C1494T, G3316A, T7510C, A7445G, and 7472insC.

Results

Our results revealed a high prevalence of mt DNA mutation (10%) in deaf families (5/50). In surprising, the unexpected mutations were observed. The G3316A mutation was found in 2 families as homoplasmic genotype. Also, we found the homoplasmic and heteroplasmic genotype for the C1494T mutation in two families. in one family the heteroplasmic genotype for T7510C mutation was observed; this family harbor 35delG mutation in GJB2 gene. None of the common mtDNA mutations (A1555G, A3243G,) and other mutations (A7445G, 7472insC) were detected here.

Conclusion

Our findings indicate to significant contribution of the mt DNA mutations in our families with NSHL. The presented data is the first report about mt DNA and it will improve the genetic counseling of hearing impaired in Syrian families.

https://ift.tt/2mCCPxx

In utero drug exposure and hearing impairment in 2-year-old children A case-control study using the EFEMERIS database

Publication date: Available online 24 July 2018

Source: International Journal of Pediatric Otorhinolaryngology

Author(s): Caroline Foch, Mélanie Araujo, Alexandra Weckel, Christine Damase-Michel, Jean-Louis Montastruc, Justine Benevent, Geneviève Durrieu, Isabelle Lacroix

https://ift.tt/2uUD36S

Association of Plasma Pentraxin-3 Levels with Retinopathy and Systemic Factors in Diabetic Patients

Metabolic Syndrome and Related Disorders, Ahead of Print.


https://ift.tt/2LvSU6g

Decreasing Disease-Specific Mortality of Differentiated Thyroid Cancer in Korea: A Multicenter Cohort Study

Thyroid, Ahead of Print.


https://ift.tt/2v0S3QH

Cardiovascular Morbidity and Mortality After Treatment of Hyperthyroidism with Either Radioactive Iodine or Thyroidectomy

Thyroid, Ahead of Print.


https://ift.tt/2LwzFJK

Pseudohyperkalemia: Hyperkalemia Cocktail or Alternative Diagnosis

Introduction. Hyperkalemia is a commonly encountered clinical problem. Pseudohyperkalemia is believed to be an in vitro phenomenon that does not reflect in vivo serum potassium and therefore should not be treated. Here, we present a case who unfortunately underwent unnecessary treatment because of failure to detect the common lab abnormality of pseudohyperkalemia. Case Presentation. A 91-year-old female with a history of chronic lymphocytic leukemia presented to the emergency with nausea and vomiting 24 hours after her first chemotherapy with chlorambucil. Physical examination was overall unremarkable. She had a leukocytosis of 210 × 103/µL with 96% lymphocytes along with chronic anemia with hemoglobin of 8.1 g/dL. Her initial sodium and potassium levels were normal. During the clinical course, her potassium progressively worsened and failed to improve despite standard medical treatment. Patient ultimately underwent dialysis. Conclusions. Differentiating true hyperkalemia from pseudohyperkalemia is very important in selected group of patients to avoid unnecessary medications, higher level of care, and unnecessary procedure including dialysis. We want to emphasize the importance of simple yet profound knowledge of technique of blood draws and basic metabolic panel processing for every clinician in day-to-day practice.

https://ift.tt/2Oe5RA3

Cardiac Involvement by HIV-Associated DLBCL

Non-Hodgkin's lymphoma (NHL) is a common AIDS-defining malignancy among people living with HIV. Of the different types of NHLs, diffuse large B-cell lymphoma (DLBCL) is the most common. Prognosis of DLBCL has improved over the years in the general population but remains relatively poor in HIV-positive individuals. Almost any organ system can be affected by DLBCL; however, cardiac involvement remains rare and suggests aggressive disease. We present a case of DLBCL in an HIV-positive patient, who had cardiac involvement, with the only clue to cardiac involvement being symptom being tachycardia and dysphagia.

https://ift.tt/2NBaT8C

Störungen des Kalziumhaushalts

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 516-528
DOI: 10.1055/s-0043-121655

Störungen des Kalziumhaushalts sind weit verbreitet. Ihre pathophysiologischen Ursachen sind sehr heterogen und die klinischen Symptome häufig unspezifisch. Daher ist eine genaue Diagnostik unerlässlich und ein schneller Ausgleich der Kalziumhomöostase essenziell. Dieser Artikel erörtert die pathophysiologischen, diagnostischen und therapeutischen Pfeiler von Hypo- und Hyperkalzämie sowie ihre Auswirkungen auf Anästhesie und Intensivmedizin.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

https://ift.tt/2LvGY4s

Videolaryngoskopie – Ende der Fiberoptik beim erwartet schwierigen Atemweg?

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 487-488
DOI: 10.1055/a-0643-3504

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

https://ift.tt/2v09YqC

Störungen des Natriumhaushalts

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 492-502
DOI: 10.1055/s-0043-121662

Störungen des Natriumhaushalts sind häufig auftretende Elektrolytimbalancen. Sowohl sie selbst als auch ihre unsachgemäße Therapie können schwerwiegende Komplikationen nach sich ziehen. Der vorliegende Artikel informiert über die Ätiologie von Störungen des Natriumhaushalts und stellt wichtige therapeutische Prinzipien dar.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

https://ift.tt/2LvGg7i

Vollelektrolyt- versus NaCl-Lösung in der Therapie kritisch kranker Erwachsener

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 488-488
DOI: 10.1055/a-0643-3479

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

https://ift.tt/2v09TTQ

Orale Antikoagulanzien: Management von elektiven und Notfalleingriffen

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 543-550
DOI: 10.1055/s-0043-111006

Orale Antikoagulation bei chirurgischen Patienten erfolgt meistens mit Vitamin-K-Antagonisten (VKA) oder nicht-Vitamin-K-antagonistischen oralen Antikoagulanzien (NOAK). Während VKA wegen ihrer langen Halbwertszeit über die INR gesteuert werden, ist bei NOAK in der Regel keine Gerinnungskontrolle notwendig. Die Gabe erfolgt in festen Dosierungen. Spezifische Gerinnungswerte zur Bestimmung der Wirkung von NOAK können über die Anti-Faktor-Xa(FXa)-Aktivität (für FXa-Inhibitoren: Apixaban, Edoxaban, Rivaroxaban) und die verdünnte Thrombinzeit (für Dabigatran) erfolgen. Es gibt aktuell keine validierten Grenzwerte, die mit einem erhöhten Risiko für perioperative Blutungen einhergehen. Während VKA perioperativ auf eine parenterale Antikoagulation (z. B. niedermolekulares Heparin) umgestellt werden („Bridging"), werden NOAK pausiert. Ebenso ist nach ausreichendem Sicherheitsabstand die Durchführung von rückenmarksnahen Regionalanästhesieverfahren möglich. Falls erforderlich können NOAK auch auf ein parenterales Verfahren umgestellt werden („Switching"). Lebensbedrohliche Blutungskomplikationen können sowohl unter VKA als auch unter NOAK mit Prothrombinkomplex (PPSB) behandelt werden. Für Dabigatran steht ein Antidot zur Verfügung.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

https://ift.tt/2LvGewc

Glukokortikoid-Therapie im septischen Schock – ja oder nein?

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 489-489
DOI: 10.1055/a-0643-3451

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

https://ift.tt/2v09Pn4

Störungen des Kaliumhaushalts

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 504-514
DOI: 10.1055/s-0043-121654

Störungen des Kaliumhaushalts sind perioperativ und beim Intensivpatienten häufig anzutreffen – sie können sich schnell zu einer akuten Lebensbedrohung entwickeln. Dieser Beitrag geht auf die physiologischen Grundlagen des Kaliumhaushalts ein und zeigt auf, wie akute Störungen behandelt werden können.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

https://ift.tt/2LzcQVU

Elektrolytstörungen

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 490-491
DOI: 10.1055/a-0631-0160

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

https://ift.tt/2uWbgDd

Neue Antibiotika für die Therapie von multiresistenten gramnegativen Bakterien

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 529-542
DOI: 10.1055/s-0043-110504

Die stetige Zunahme an bakteriellen Resistenzen und von multiresistenten Erregern (MRE) – vor allem im gramnegativen Bereich – ist ein weltweites Problem. Die Entwicklung neuer Wirkstoffe gegen Infektionen mit multiresistenten gramnegativen Erregern (MRGN) besitzt daher höchste Priorität. Im Folgenden werden kürzlich zugelassene oder in der fortgeschrittenen klinischen Prüfung befindliche Antibiotika mit Wirksamkeit gegen MRGN vorgestellt.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

https://ift.tt/2LwYPrC

Versorgung von Traumapatienten mit dem „REBEL“-Set

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 551-558
DOI: 10.1055/s-0044-102122

Die zunehmende Terrorbedrohung und ein verändertes Einsatzspektrum für den Rettungsdienst erfordern eine Anpassung und Erweiterung von Notfallrettungsmitteln und Einsatztaktik. Ein Beispiel hierfür ist die bayerische „Handlungsempfehlung für Rettungsdienst bei besonderen Einsatzlagen (REBEL)". Es werden 3 Fälle vorgestellt, bei denen „neue Hilfsmittel" wie Hämostyptika, Thoraxverschlusspflaster und Tourniquet aus dem REBEL-Set bei Rettungsdiensteinsätzen angewandt wurden.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

https://ift.tt/2v0On1p

Gefährliche Patientenübergaben!

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 486-487
DOI: 10.1055/a-0643-3517

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

https://ift.tt/2LsXpyx

FcεRI cross-linking and IL-3 protect human basophils from intrinsic apoptotic stress

Publication date: Available online 23 July 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Lionel Rohner, Ramona Reinhart, Björn Hagmann, Andrea Odermatt, Annet Babirye, Thomas Kaufmann, Michaela Fux

https://ift.tt/2JTZa2Y

Hypoxia disrupts aryl hydrocarbon receptor signaling and the Th17 response in allergic rhinitis patients

Publication date: September 2018

Source: Molecular Immunology, Volume 101

Author(s): Wei Kou, Xuelei Li, Hongbing Yao, Cheng Zhang, Ping Wei

Abstract

Background

Hypoxic conditions area key feature of allergic rhinitis (AR), however, the role of hypoxia in AR remains to be fully understood. The aim of this study was to survey the effect of hypoxia on the Th17 response in AR patients by investigating the action of hypoxia-influenced signaling pathways on Th17 differentiation.

Methods

23 AR patients and 15 healthy controls were recruited for this study. Under normoxia and hypoxic conditions, the expression of HIF-1α, AhR, CYP1A1 and CYP1B1 and the presence of Th17 cells in CD4⁺T cells were measured. Furthermore, the amount of ARNT combined with either HIF-1α or AhR was determined after the exposure of 2-(1H-Indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl easter (ITE) with normoxia and hypoxia.

Results

HIF-1α and AhR expression were higher in CD4⁺T cells from AR patients than in those from healthy controls. In a hypoxic environment, the expression of HIF-1α was elevated in CD4⁺T cells of both AR patients and healthy controls. Meanwhile, the suppressive effects of a non-toxic AhR ligand (ITE) on the Th17 response and its positive effects on IL-10 production were suppressed in the cells of AR patients and healthy controls under hypoxia. These effects were arisen from HIF-1α out-competing AhR for ARNT binding which limited the activity of the AhR pathway.

Conclusions

The present results suggest that hypoxia is capable of promoting the Th17 response by reducing AhR activity via HIF-1α activity. Thus hypoxia may be intimately involved in the pathogenesis of AR.

https://ift.tt/2v0Ezo7

Nail photography tricks for pediatric and geriatric patients

https://ift.tt/2NECRjI

Methods for Decreasing the Incidence of Moist Desquamation in Patients Undergoing Radiotherapy

https://ift.tt/2OcKDTe

Lightening Becker’s Nevus with Topical Glycolic Acid

https://ift.tt/2NEj8ko

Sirolimus for treatment of verrucous venous malformation: A retrospective cohort study

https://ift.tt/2O6kgOR

Small oral tongue cancers (≤ 4 cm in diameter) with clinically negative neck: from the 7th to the 8th edition of the American Joint Committee on Cancer

Abstract

One of the main changes in the 8th edition of the American Joint Committee on Cancer (AJCC) for staging of oral cancer is the inclusion of depth of invasion (DOI) in the T category. However, cancers in different oral subsites have variable behavior, with oral tongue squamous cell carcinoma (OTSCC) being the most aggressive one even at early stage. Thus, it is necessary to evaluate the performance of this new T category in homogenous cohort of early OTSCC. Therefore, we analyzed a large cohort of patients with a small (≤ 4 cm) OTSCC to demonstrate the differences in T stage between the AJCC 7th and 8th editions. A total of 311 early-stage cases (AJCC 7th) of OTSCC were analyzed. We used 5 mm and 10 mm DOI for upstaging from T1 to T2 and from T2 to T3 respectively, as in the AJCC 8th. We further reclassified the cases according to our own proposal suggesting 2 mm to upstage to T2 and 4 mm to upstage to T3. According to AJCC 7th, there were no significant differences in the survival analysis. When we applied the 8th edition, many cases were upstaged to T3 and thus associated with worse disease-specific survival (HR 2.37, 95% CI 1.12–4.99) and disease-free survival (HR 2.12, 95% CI 1.09–4.08). Based on our proposal, T3 cases were associated with even worse disease-specific survival (HR 4.19, 95% CI 2.27–7.74). The 8th edition provides better survival prediction for OTSCC than the 7th and can be further optimized by lowering the DOI cutoffs.

https://ift.tt/2mDOVGN

The co-identification of mcr-4.6 and blaNDM-1 in a clinical Enterobacter cloacae isolate from China [PublishAheadOfPrint]

Here we describe the first report of a clinical colistin-resistant ST84 Enterobacter cloacae isolate co-harboring mcr-4.6 (previously named mcr-4.2) and bla_NDM-1 from a patient in China. The bla_NDM-1-harboring IncX3 plasmid and the novel mcr-4.6-harboring ColE plasmid were completely sequenced. Although this isolate showed high level resistance to colistin, mcr-4.6 plasmid transformation, gene subcloning, susceptibility testing and lipid A matrix-assisted laser desorption ionization mass spectrometry analysis indicate that mcr-4.6 itself doesn't confer resistance to colistin.

https://ift.tt/2mC9CTl

Various sequence types of Enterobacteriaceae carrying blaNDM-5 gene from commercial chicken farms in China [PublishAheadOfPrint]

A total of 108 meropenem-resistant Enterobacteriaceae isolates were obtained from 1658 rectal swabs collected from 15 unrelated commercial chicken farms in China between 2014 and 2016. These samples yielded sixteen Escherichia coli and two Klebsiella pneumoniae isolates of diverse sequence types carrying a bla_NDM-5-bearing IncX3 plasmid. Klebsiella pneumoniae strain sequence type 709 (ST709) has two bla_NDM-5-carrying plasmids that were transferred together to E.coli.

https://ift.tt/2A6k9Qo

Relative Contribution of the ABC Transporters Cdr1, Pdh1, and Snq2 to Azole Resistance in Candida glabrata [PublishAheadOfPrint]

The utility of the azole antifungals for the treatment of invasive candidiasis is severely hampered by azole resistance in Candida glabrata. This resistance is mediated almost exclusively by activating mutations in the zinc cluster transcription factor Pdr1, which controls the genes encoding the multidrug resistance transporters Cdr1, Pdh1, and Snq2. However, the specific relative contribution of these transporters to resistance is not known. To address this question, the SAT1 flipper method was used to delete CDR1, PDH1, and SNQ2 in a strain of C. glabrata engineered to carry a clinically relevant activating mutation in PDR1. Susceptibility testing was performed according to the CLSI guidelines with minor modifications and confirmed with Etest strips. Of the single transporter deletion strains, only CDR1 deletion resulted in decreased azole MIC. Deletion of PDH1 in combination with CDR1 resulted in a moderate decrease in MIC from that observed with deletion of CDR1 alone. SNQ2 deletion only decreased the MIC in the triple deletion strain in the absence of both CDR1 and PDH1. Deletion of all three transporters in combination decreased the MIC to the level observed in the PDR1 deletion strains for some, but not all azoles tested, which indicates additional Pdr1 targets likely play a minor role in this process. These results indicate that while Cdr1 is the most important Pdr1-mediated multidrug resistance transporter for azole resistance in this clinical isolate, all three of these transporters contribute to its high-level resistance to the azole antifungals.

https://ift.tt/2mC9xz1

Lysostaphin lysibody leads to effective opsonization and killing of methicillin resistant Staphylococcus aureus in a murine model [PublishAheadOfPrint]

The cell wall of Gram-positive bacteria contains abundant surface-exposed carbohydrate structures that are highly conserved. While these properties make surface carbohydrates ideal targets for immunotherapy, carbohydrates elicit a poor immune response resulting primarily in low-affinity IgM antibodies. In a previous publication we introduced the lysibody approach to address this shortcoming. Lysibodies are engineered molecules that combine a high-affinity carbohydrate-binding domain from bacterial or bacteriophage origin and an Fc effector portion of a human IgG antibody, thus directing effective immunity to conserved bacterial surface carbohydrates. Here, we describe the first example of a lysibody containing the binding domain from a bacteriocin – lysostaphin. We also describe the creation of five lysibodies with binding domains derived from phage lysins, directed against Staphylococcus aureus. The lysostaphin and LysK lysibodies showed the most promise and were further characterized. Both lysibodies bound a range of clinically important staphylococcal strains, fixed complement on the staphylococcal surface, and induced phagocytosis of S. aureus by macrophages and human neutrophils. The lysostaphin lysibody had superior in vitro activity compared to the LysK lysibody as well as the previously characterized ClyS lysibody, and effectively protected mice in a kidney abscess/bacteremia model. These results further demonstrate that the lysibody approach is a reproducible means of creating anti-bacterial antibodies that cannot be produced by conventional means. Lysibodies therefore are a promising solution for opsonic antibodies that may be used passively to both treat and prevent infection by drug-resistant pathogens.

https://ift.tt/2uYRuHc

No Resistance to Tenofovir Alafenamide Detected Through 96 Weeks of Treatment in Patients with Chronic Hepatitis B [PublishAheadOfPrint]

Tenofovir alafenamide (TAF) has shown equivalent efficacy and improved safety profiles for patients with chronic hepatitis B (CHB) compared to tenofovir disoproxil fumarate (TDF). However, limited data are available for its resistance profiles. In 2 clinical trials, 1298 HBeAg-positive and HBeAg-negative patients with CHB were randomized 2:1 and treated with TAF (n=866) or TDF (n=432). Baseline nucleos(t)ide analog resistance substitutions in HBV polymerase/reverse transcriptase (pol/RT) were assessed using INNO-LiPA Multi DR v2/v3. Resistance surveillance was conducted for patients with viremia (HBV DNA ≥69IU/mL) by HBV pol/RT sequencing at week 96 or at discontinuation. In vitro phenotypic analysis was performed for patients with conserved site substitutions or virologic breakthrough while adherent to study drug. At baseline, the majority of patients harbored virus with wild type pol/RT (89.2%), with 10.8% harboring resistance associated mutations. A similar percentage of patients in the TAF or TDF groups qualified for sequence analysis through week 96 (TAF 11.1%, TDF 10.9%). Of these, a small percentage of patients experienced virologic breakthrough (TAF: 2.8%, TDF: 3.2%) that was often associated with drug nonadherence (TAF: 30%, TDF: 50%). Across treatment groups, 132 patients qualified for sequence analysis through week 96 with nearly half having no sequence changes from baseline (43.2%). Most sequence changes occurred at polymorphic positions, and no isolates showed a reduction in susceptibility in vitro. After 96 weeks, the proportion of patients achieving virus suppression (HBV DNA <69 IU/mL) was similar across treatment groups and no substitutions associated with resistance to TAF or TDF were detected.

https://ift.tt/2mC9ovt

Effects of phage endolysin SAL200 combined with antibiotics on Staphylococcus aureus infection [PublishAheadOfPrint]

Phages and its derivatives are increasingly reconsidered for the treatment of bacterial infections, due to rising antibiotic resistance. We assessed the anti-staphylococcal effect of the endolysin SAL200 in combination with standard-of-care (SOC) antibiotics. SAL200 activity combined with SOC antibiotics was assessed in vitro by checkerboard and time-kill assays, and in vivo with murine bacteremia and Galleria mellonella infection models. SAL200 reduced SOC antibiotic MICs and showed a ≥3-log₁₀CFU/mL reduction of S. aureus within 30 minutes in time-kill assays. Combinations of SAL200 and SOC antibiotics achieved a sustained decrease of >2-log₁₀CFU/mL. SAL200 significantly lowered blood bacterial density within 1 hour by > 1 log₁₀CFU/mL in bacteremic mice (P<0.05 vs untreated mice), and SAL200 and SOC antibiotic combinations achieved the lowest levels of bacteremia. Bacterial density in splenic tissue at 72 h post-infection was lowest in mice treated with SAL200 and SOC antibiotic combinations. SAL200 combined with SOC antibiotics also improved Galleria mellonella larvae survival at 96 h post-infection.

The combination of phage endolysin SAL200 with SOC anti-staphylococcal antibiotics showed synergistic effects in vitro and in vivo. The combination of SAL200 with SOC antibiotics could help in the treatment of difficult S. aureus infections.

https://ift.tt/2A0ug96

In Vitro Activity of LYS228, a Novel Monobactam Antibiotic, against Multidrug-resistant Enterobacteriaceae [PublishAheadOfPrint]

LYS228 is a novel monobactam with potent activity against Enterobacteriaceae. LYS228 is stable to metallo-β-lactamases (MBLs) and serine carbapenemases, including Klebsiella pneumoniae carbapenemases (KPCs), resulting in potency against the majority of extended spectrum β-lactamase (ESBL)-producing and carbapenem-resistant Enterobacteriaceae (CRE) strains tested. Overall, LYS228 demonstrated potent activity against 271 Enterobacteriaceae strains, including multidrug-resistant isolates. Based upon MIC₉₀ values, LYS228 (MIC₉₀= 1 μg/mL) was ≥32-fold more active against these strains than were aztreonam, ceftazidime, ceftazidime/avibactam, cefepime, and meropenem. The MIC₉₀ value for tigecyline was 4 μg/mL against the strains tested. Against Enterobacteriaceae isolates expressing ESBLs (N=37) or displaying carbapenem resistance (N=77), LYS228 had MIC₉₀ values of 1 and 4 μg/mL, respectively.

LYS228 exhibited potent bactericidal activity as indicated by low MBC to MIC ratios (≤4) against 97.4% (264/271) of the Enterobacteriaceae strains tested. In time-kill studies, LYS228 consistently achieved 3-log₁₀ reduction in colony-forming units (CFU)/mL (≥99.9% killing) at concentrations ≥4X the MIC for E. coli and K. pneumoniae reference strains as well as isolates encoding TEM-1, SHV-1, CTX-M-14, CTX-M-15, KPC-2, KPC-3 and NDM-1 β-lactamases.

https://ift.tt/2mByjiF

Population Pharmacokinetics of the Antimalarial Amodiaquine: A Pooled Analysis to Optimize Dosing [PublishAheadOfPrint]

Amodiaquine plus artesunate is the recommended antimalarial treatment in many malaria-endemic countries. However, pediatric doses are largely based on a linear extrapolation from adult doses. We pooled data from previously published studies on the pharmacokinetics of amodiaquine, to optimize the dose across all age groups. Adults and children with uncomplicated malaria received daily weight-based doses of amodiaquine or artesunate-amodiaquine over three days. Plasma concentration-time profiles for both parent drug and metabolite were characterized using nonlinear mixed-effects modelling. Amodiaquine pharmacokinetics was adequately described by a two-compartment disposition model, with first-order elimination leading to the formation of desethylamodiaquine, which was best described by a three-compartment disposition model. Body size and age were the main covariates affecting amodiaquine clearance. After adjusting for the effect of weight, clearance rates for amodiaquine and desethylamodiaquine reached 50% of adult maturation at 2.8 (95% CI: 1.5 – 3.7) and 3.9 (95% CI: 2.6 – 5.3) months after birth, assuming a baby born at term. Bioavailability was 22.4% (15.6 – 31.9%) lower at the start of treatment than during convalescence, which suggests a malaria disease effect. Neither drug formulation nor hemoglobin had an effect on any pharmacokinetic parameters. Results from simulations showed that current manufacturer dosing recommendations resulted in low desethylamodiaquine exposure in patients weighing 8 kg, 15 – 17 kg, 33 – 35 kg, and in patients > 62 kg compared to a typical 50 kg patient. We propose possible optimized dosing regimens to achieve similar drug exposures among all age groups, which require further validation.

https://ift.tt/2Abjkpc

Tolerability of prosthetic joint infection empirical antimicrobial therapy: a prospective cohort study [PublishAheadOfPrint]

Objectives: The empirical use of vancomycin in combination with a broad-spectrum betalactam is currently recommended after the initial surgery of prosthetic joint infection (PJI). However, the tolerability of such high-dose intravenous regimens is poorly known.

Patient and methods: Adult patients receiving an empirical antimicrobial therapy (EAT) for a PJI were enrolled in a prospective cohort study (2011-2016). EAT-related adverse events (AE) were described according to the common terminology criteria for AE (CTCAE), and their determinants were assessed by logistic regression and Kaplan-Meier curve analysis.

Results: The EAT of the 333 included patients (median age, 69.8 (IQR, 59.3-79.1)) mostly relies on vancomycin (n=229, 68.8%), piperacillin/tazobactam (n=131, 39.3%) and/or 3^rdGC (n=50, 15%). Forty-two (12.6%) experienced an EAT-related AE. Ten (20.4%) AE were severe (CTCAE grade ≥3). The use of vancomycin (OR, 6.9; 95%CI, 2.1-22.9), piperacillin/tazobactam (OR, 3.7; 95%CI, 1.8-7.2) or the combination of both (OR, 4.1; 95%CI, 2.1-8.2) were the only AE predictors. Acute kidney injury (AKI) was the most frequent AE (n=25; 51.0% of AE), and was also associated with the use of the vancomycin and piperacillin/tazobactam combination (OR, 6.7; 95%CI, 2.6-17.3). A vancomycin plasma overexposure was noted in 9 (37.5%) of the vancomycin-related AKI, only. Other vancomycin-based therapies were significantly less at risk of AE and AKI.

Conclusions: The EAT of PJI is associated with an important rate of AE, linked with the use of the vancomycin and piperacillin/tazobactam combination. These results corroborate recent finding suggesting a synergic toxicity of these drugs in comparison with vancomycin-cefepime, which remain to be evaluated in PJI.

https://ift.tt/2mC9cwf

Neck stiffness in a post-irradiated nasopharyngeal carcinoma adult: An unusual diagnosis

Nasopharyngeal carcinoma is a neoplasm commonly found in population of South East Asia. The mainstay of treatment is high dose irradiation. Complications from radiotherapy are not uncommon especially to those nearby structures such as vertebrae and spinal cord. A 57 year-old gentleman with nasopharyngeal carcinoma (NPC) who was treated with chemo-radiation (total of 35 fractions,70Gy) presented to us 6 months post therapy with bilateral nasal discharge and progressive neck stiffness. Nasoendoscopy showed inflamed nasophayngeal mucosa and Computed Tomography (CT) brain and cervical spine showed retropharyngeal and anterior epidural collection with extension into atlantoaxial bone and spinal cord compression.

https://ift.tt/2JNIjyo

Leishmania donovani Exploits Tollip, a Multitasking Protein, To Impair TLR/IL-1R Signaling for Its Survival in the Host [INFECTIOUS DISEASE AND HOST RESPONSE]

IL-1R/TLR signaling plays a significant role in sensing harmful foreign pathogens and mounting effective innate and adaptive immune responses. However, the precise mechanism by which Leishmania donovani, an obligate intramacrophagic pathogen, breaches IL-1R/TLR signaling and host-protective immunity remains obscure. In this study, we report the novel biphasic role of Toll-interacting protein (Tollip), a negative regulator of the IL-1R/TLR pathway, in the disease progression of experimental visceral leishmaniasis. We observed that during early hours of infection, L. donovani induced phosphorylation of IRAK-1, resulting in the release of Tollip from the IL-1R–associated kinase (IRAK)-1 complex in J774 macrophages, which then acted as an endocytic adaptor on cell surface IL-1R1 and promoted its lysosomal degradation. In the later stage, Tollip shuttled back to IRAK-1, thereby inhibiting IRAK-1 phosphorylation in association with IRAK-M to neutralize downstream TLR signaling in infected macrophages. Moreover, during late infection, L. donovani enhanced nuclear translocation and recruitment of transcription factors early growth response protein 2, NF erythroid 2–related factor 2, and Ahr on Tollip promoter for its induction. Small interfering RNA–mediated silencing of Tollip in infected macrophages significantly enhanced NF-B activation and induced host-defensive IL-12 and TNF-α synthesis, thereby reducing amastigote multiplication. Likewise, abrogation of Tollip in L. donovani–infected BALB/c mice resulted in STAT-1–, IRF-1–, and NF-B–mediated upregulation of host-protective cytokines and reduced organ parasite burden, thereby implicating its role in disease aggravation. Taken together, we conclude that L. donovani exploited the multitasking function of Tollip for its own establishment through downregulating IL-1R1/TLR signaling in macrophages.

https://ift.tt/2mBpp4J

From Cancer Immune Surveillance to Cancer Immunoediting: Birth of Modern Immuno-Oncology [PILLARS OF IMMUNOLOGY]

https://ift.tt/2mAVr0G

Widespread Effects of Chemokine 3' Untranslated Regions on mRNA Degradation and Protein Production in Human Cells [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

Chemokines are a large family of chemotactic cytokines that play critical roles in inflammation, development, and diseases. Chemokine expression is highly regulated during development and in response to environmental stimuli. The 3' untranslated regions (3'-UTRs) of mRNA are believed to be important in the control of chemokine gene expression. However, the regulatory effects of most chemokine 3'-UTRs have not been characterized previously. In this work, we systematically studied the effects of 43 CC and CXC chemokine 3'-UTRs on gene expression in eight human cell lines and two types of human primary cells. We found that chemokine 3'-UTRs had a wide spectrum of regulatory effects on mRNA abundance and protein production that were tightly correlated with the effects on mRNA stability. In general, 3'-UTRs had remarkably similar effects across all cell types studied. The presence of AU-rich elements, microRNA targets, and Pumilio binding sites were associated with chemokine 3'-UTR activity but did not fully account for all 3'-UTR activity detected using the reporter assay. Mutational analysis illustrated how specific cis-regulatory elements contributed to the regulatory effect of chemokine 3'-UTRs. These findings bring new insights into the mechanisms by which chemokine expression is regulated by 3'-UTRs.

https://ift.tt/2mCjBIk

Pillars Article: IFN{gamma} and Lymphocytes Prevent Primary Tumour Development and Shape Tumour Immunogenicity. Nature. 2001. 410: 1107-1111 [PILLARS OF IMMUNOLOGY]

https://ift.tt/2uXQm6E

Collagen VI Contains Multiple Host Defense Peptides with Potent In Vivo Activity [INNATE IMMUNITY AND INFLAMMATION]

Collagen VI is a ubiquitous extracellular matrix component that forms extensive microfibrillar networks in most connective tissues. In this study, we describe for the first time, to our knowledge, that the collagen VI von Willebrand factor type A–like domains exhibit a broad-spectrum antimicrobial activity against Gram-positive and Gram-negative bacteria in human skin infections in vivo. In silico sequence and structural analysis of VWA domains revealed that they contain cationic and amphipathic peptide sequence motifs, which might explain the antimicrobial nature of collagen VI. In vitro and in vivo studies show that these peptides exhibited significant antibacterial activity against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa through membrane disruption. Our findings shed new light on the role of collagen VI–derived peptides in innate host defense and provide templates for development of peptide-based antibacterial therapies.

https://ift.tt/2mBX4vd

Ebola Immunity: Gaining a Winning Position in Lightning Chess [BRIEF REVIEWS]

Zaire ebolavirus (EBOV), one of five species in the genus Ebolavirus, is the causative agent of the hemorrhagic fever disease epidemic that claimed more than 11,000 lives from 2014 to 2016 in West Africa. The combination of EBOV's ability to disseminate broadly and rapidly within the host and its high pathogenicity pose unique challenges to the human immune system postinfection. Potential transmission from apparently healthy EBOV survivors reported in the recent epidemic raises questions about EBOV persistence and immune surveillance mechanisms. Clinical, virological, and immunological data collected since the West Africa epidemic have greatly enhanced our knowledge of host–virus interactions. However, critical knowledge gaps remain in our understanding of what is necessary for an effective host immune response for protection against, or for clearance of, EBOV infection. This review provides an overview of immune responses against EBOV and discusses those associated with the success or failure to control EBOV infection.

https://ift.tt/2mEzYUW

Multiplexed Division Tracking Dyes for Proliferation-Based Clonal Lineage Tracing [NOVEL IMMUNOLOGICAL METHODS]

The generation of cellular heterogeneity is an essential feature of immune responses. Understanding the heritability and asymmetry of phenotypic changes throughout this process requires determination of clonal-level contributions to fate selection. Evaluating intraclonal and interclonal heterogeneity and the influence of distinct fate determinants in large numbers of cell lineages, however, is usually laborious, requiring familial tracing and fate mapping. In this study, we introduce a novel, accessible, high-throughput method for measuring familial fate changes with accompanying statistical tools for testing hypotheses. The method combines multiplexing of division tracking dyes with detection of phenotypic markers to reveal clonal lineage properties. We illustrate the method by studying in vitro–activated mouse CD8⁺ T cell cultures, reporting division and phenotypic changes at the level of families. This approach has broad utility as it is flexible and adaptable to many cell types and to modifications of in vitro, and potentially in vivo, fate monitoring systems.

https://ift.tt/2mDDXB7

Cutting Edge: Critical Roles for Microbiota-Mediated Regulation of the Immune System in a Prenatal Immune Activation Model of Autism [CUTTING EDGE]

Recent studies suggest that autism is often associated with dysregulated immune responses and altered microbiota composition. This has led to growing speculation about potential roles for hyperactive immune responses and the microbiome in autism. Yet how microbiome–immune cross-talk contributes to neurodevelopmental disorders currently remains poorly understood. In this study, we report critical roles for prenatal microbiota composition in the development of behavioral abnormalities in a murine maternal immune activation (MIA) model of autism that is driven by the viral mimetic polyinosinic-polycytidylic acid. We show that preconception microbiota transplantation can transfer susceptibility to MIA-associated neurodevelopmental disease and that this is associated with modulation of the maternal immune response. Furthermore, we find that ablation of IL-17a signaling provides protection against the development of neurodevelopmental abnormalities in MIA offspring. Our findings suggest that microbiota landscape can influence MIA-induced neurodevelopmental disease pathogenesis and that this occurs as a result of microflora-associated calibration of gestational IL-17a responses.

https://ift.tt/2uXQcfy

Rhabdovirus-Inducible MicroRNA-210 Modulates Antiviral Innate Immune Response via Targeting STING/MITA in Fish [INFECTIOUS DISEASE AND HOST RESPONSE]

Viral infection induces type I IFN production, which plays critical roles in orchestrating the antiviral defense by inducing direct antiviral activities. To establish a persistent infection, viruses have evolved numerous strategies to specifically interfere with IFN production or its downstream mediators, thereby evading the immune responses. MicroRNAs (miRNAs) are a family of small noncoding RNAs that posttranscriptionally regulate the expressions of specific target genes. Although accumulating evidence demonstrates that miRNAs play vital roles in regulating viral infection, miRNAs that target intracellular sensors and adaptors of innate immunity have not been fully uncovered. In this paper, we identify fish miR-210 as a robust regulator involved in regulating virus–host interactions. We found that rhabdovirus significantly upregulated the expression of fish miR-210. Inducible miR-210 modulates virus-triggered type I IFN and inflammatory cytokine production by targeting stimulator of IFN genes (STING), thereby promoting viral replication. Furthermore, we demonstrated that miR-210 regulates innate immune response through NF-B, IFN regulatory factor 3, and JAK/STAT signaling pathways. The collective findings indicate that inducible miR-210 plays a regulatory role in virus–host interactions through STING-mediated singling pathway by targeting STING.

https://ift.tt/2mBpoxH

Repeated Allergen Exposure in A/J Mice Causes Steroid-Insensitive Asthma via a Defect in Glucocorticoid Receptor Bioavailability [ALLERGY AND OTHER HYPERSENSITIVITIES]

The importance of developing new animal models to assess the pathogenesis of glucocorticoid (GC)-insensitive asthma has been stressed. Because of the asthma-prone background of A/J mice, we hypothesized that asthma changes in these animals would be or become resistant to GCs under repeated exposures to an allergen. A/J mice were challenged with OVA for 2 or 4 consecutive d, starting on day 19 postsensitization. Oral dexamethasone or inhaled budesonide were given 1 h before challenge, and analyses were done 24 h after the last challenge. Airway hyperreactivity, leukocyte infiltration, tissue remodeling, and cytokine levels as well as phosphorylated GC receptor (p-GCR), p-GATA-3, p-p38, MAPK phosphatase-1 (MKP-1), and GC-induced leucine zipper (GILZ) levels were assessed. A/J mice subjected to two daily consecutive challenges reacted with airway hyperreactivity, subepithelial fibrosis, and marked accumulation of eosinophils in both bronchoalveolar lavage fluid and peribronchial space, all of which were clearly sensitive to dexamethasone and budesonide. Conversely, under four provocations, most of these changes were steroid resistant. A significant reduction in p-GCR/GCR ratio following 4- but not 2-d treatment was observed, as compared with untreated positive control. Accordingly, steroid efficacy to transactivate MKP-1 and GILZ and to downregulate p-p38, p-GATA-3 as well as proinflammatory cytokine levels was also seen after two but not four provocations. In conclusion, we report that repeated allergen exposure causes GC-insensitive asthma in A/J mice in a mechanism associated with decrease in GCR availability and subsequent loss of steroid capacity to modulate pivotal regulatory proteins, such as GATA-3, p-p38, MKP-1, and GILZ.

https://ift.tt/2mEv0Yk

Ligation of the CD44 Glycoform HCELL on Culture-Expanded Human Monocyte-Derived Dendritic Cells Programs Transendothelial Migration [INNATE IMMUNITY AND INFLAMMATION]

The success of dendritic cell (DC)–based immunotherapeutics critically hinges on the capacity of the vascularly administered cells to enter tissues. Transendothelial migration (TEM) is dictated by an ordered cascade of receptor/ligand interactions. In this study, we examined the key molecular effectors of TEM of human monocyte-derived DCs (mo-DCs) generated by clinically relevant methods: CD14 selection (CD14-S) and plastic adherence selection (PA-S). Without chemokine input, CD14-S cells undergo greater TEM than PA-S cells over TNF-α–stimulated HUVECs. TEM of CD14-S mo-DCs is E-selectin/very late Ag-4 (VLA-4) dependent, and engagement of E-selectin ligands activates VLA-4 on CD14-S mo-DCs but not on PA-S mo-DCs. E-selectin binding glycoforms of P-selectin glycoprotein ligand-1 (PSGL-1) (i.e., cutaneous lymphocyte Ag [CLA]) and CD44 (i.e., hematopoietic cell E-selectin/L-selectin ligand [HCELL]) are both expressed on CD14-S mo-DCs, but only CLA is expressed on PA-S mo-DCs. To elucidate the effect of CD44 or PSGL-1 engagement, mo-DCs were pretreated with their ligands. Ligation of CD44 on CD14-S mo-DCs triggers VLA-4 activation and TEM, whereas PSGL-1 ligation does not. HCELL expression on CD14-S mo-DC can be enforced by cell surface exofucosylation, yielding increased TEM in vitro and enhanced extravasation into bone marrow in vivo. These findings highlight structural and functional pleiotropism of CD44 in priming TEM of mo-DCs and suggest that strategies to enforce HCELL expression may boost TEM of systemically administered CD14-S mo-DCs.

https://ift.tt/2mBpohb

Anti-Insulin B Cells Are Poised for Antigen Presentation in Type 1 Diabetes [AUTOIMMUNITY]

Early breaches in B cell tolerance are central to type 1 diabetes progression in mouse and man. Conventional BCR transgenic mouse models (VH125.Tg NOD) reveal the power of B cell specificity to drive disease as APCs. However, in conventional fixed IgM models, comprehensive assessment of B cell development is limited. To provide more accurate insight into the developmental and functional fates of anti-insulin B cells, we generated a new NOD model (V_H125^SD.NOD) in which anti-insulin VDJH125 is targeted to the IgH chain locus to generate a small (1–2%) population of class switch–competent insulin-binding B cells. Tracking of this rare population in a polyclonal repertoire reveals that anti-insulin B cells are preferentially skewed into marginal zone and late transitional subsets known to have increased sensitivity to proinflammatory signals. Additionally, IL-10 production, characteristic of regulatory B cell subsets, is increased. In contrast to conventional models, class switch–competent anti-insulin B cells proliferate normally in response to mitogenic stimuli but remain functionally silent for insulin autoantibody production. Diabetes development is accelerated, which demonstrates the power of anti-insulin B cells to exacerbate disease without differentiation into Ab-forming or plasma cells. Autoreactive T cell responses in V_H125^SD.NOD mice are not restricted to insulin autoantigens, as evidenced by increased IFN- production to a broad array of diabetes-associated epitopes. Together, these results independently validate the pathogenic role of anti-insulin B cells in type 1 diabetes, underscore their diverse developmental fates, and demonstrate the pathologic potential of coupling a critical β cell specificity to predominantly proinflammatory Ag-presenting B cell subsets.

https://ift.tt/2uXQbIw

Kidney Proximal Tubular TLR9 Exacerbates Ischemic Acute Kidney Injury [TRANSPLANTATION]

The role for kidney TLR9 in ischemic acute kidney injury (AKI) remains unclear. In this study, we tested the hypothesis that renal proximal tubular TLR9 activation exacerbates ischemic AKI by promoting renal tubular epithelial apoptosis and inflammation. To test this hypothesis, we generated mice lacking TLR9 in renal proximal tubules (TLR9^fl/fl PEPCK Cre mice). Contrasting previous studies in global TLR9 knockout mice, mice lacking renal proximal tubular TLR9 were protected against renal ischemia/reperfusion (IR) injury, with reduced renal tubular necrosis, inflammation (decreased proinflammatory cytokine synthesis and neutrophil infiltration), and apoptosis (decreased DNA fragmentation and caspase activation) when compared with wild-type (TLR9^fl/fl) mice. Consistent with this, a selective TLR9 agonist oligonucleotide 1668 exacerbated renal IR injury in TLR9^fl/fl mice but not in renal proximal tubular TLR9-null mice. Furthermore, in cultured human and mouse proximal tubule cells, TLR9-selective ligands induced NF-B activation, proinflammatory cytokine mRNA synthesis, as well as caspase activation. We further confirm in the present study that global TLR9 deficiency had no impact on murine ischemic AKI. Taken together, our studies show that renal proximal tubular TLR9 activation exacerbates ischemic AKI by promoting renal tubular inflammation, apoptosis as well as necrosis, after IR via NF-B and caspase activation. Our studies further suggest the complex nature of TLR9 activation, as renal tubular epithelial TLR9 promotes cell injury and death whereas TLR9 signaling in other cell types may promote cytoprotective effects.

https://ift.tt/2mC0DkY

Breakdown of Immune Tolerance in AIRE-Deficient Rats Induces a Severe Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy-like Autoimmune Disease [AUTOIMMUNITY]

Autoimmune regulator (AIRE) deficiency in humans induces a life-threatening generalized autoimmune disease called autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), and no curative treatments are available. Several models of AIRE-deficient mice have been generated, and although they have been useful in understanding the role of AIRE in central tolerance, they do not reproduce accurately the APECED symptoms, and thus there is still a need for an animal model displaying APECED-like disease. We assessed, in this study, the potential of the rat as an accurate model for APECED. In this study, we demonstrate that in rat, AIRE is expressed by MHC class II (MCH-II)⁺ and MHC-II^– medullary thymic epithelial cells in thymus and by CD4^int conventional dendritic cells in periphery. To our knowledge, we generated the first AIRE-deficient rat model using zinc-finger nucleases and demonstrated that they display several of the key symptoms of APECED disease, including alopecia, skin depigmentation, and nail dystrophy, independently of the genetic background. We observed severe autoimmune lesions in a large spectrum of organs, in particular in the pancreas, and identified several autoantibodies in organs and cytokines such as type I IFNs and IL-17 at levels similar to APECED. Finally, we demonstrated a biased Ab response to IgG1, IgM, and IgA isotypes. Altogether, our data demonstrate that AIRE-deficient rat is a relevant APECED animal model, opening new opportunity to test curative therapeutic treatments.

https://ift.tt/2mBpw09

In This Issue [IN THIS ISSUE]

https://ift.tt/2A4cmCF

A Diverse Lipid Antigen-Specific TCR Repertoire Is Clonally Expanded during Active Tuberculosis [CLINICAL AND HUMAN IMMUNOLOGY]

Human T cells that recognize lipid Ags presented by highly conserved CD1 proteins often express semi-invariant TCRs, but the true diversity of lipid Ag–specific TCRs remains unknown. We use CD1b tetramers and high-throughput immunosequencing to analyze thousands of TCRs from ex vivo–sorted or in vitro–expanded T cells specific for the mycobacterial lipid Ag, glucose monomycolate. Our results reveal a surprisingly diverse repertoire resulting from editing of germline-encoded gene rearrangements analogous to MHC-restricted TCRs. We used a distance-based metric (TCRDist) to show how this diverse TCR repertoire builds upon previously reported conserved motifs by including subject-specific TCRs. In a South African cohort, we show that TCRDist can identify clonal expansion of diverse glucose monomycolate–specific TCRs and accurately distinguish patients with active tuberculosis from control subjects. These data suggest that similar mechanisms govern the selection and expansion of peptide and lipid Ag–specific T cells despite the nonpolymorphic nature of CD1.

https://ift.tt/2uXQ9jS

Immune Checkpoint Blockade Restores HIV-Specific CD4 T Cell Help for NK Cells [INFECTIOUS DISEASE AND HOST RESPONSE]

Immune exhaustion is an important feature of chronic infections, such as HIV, and a barrier to effective immunity against cancer. This dysfunction is in part controlled by inhibitory immune checkpoints. Blockade of the PD-1 or IL-10 pathways can reinvigorate HIV-specific CD4 T cell function in vitro, as measured by cytokine secretion and proliferative responses upon Ag stimulation. However, whether this restoration of HIV-specific CD4 T cells can improve help to other cell subsets impaired in HIV infection remains to be determined. In this study, we examine a cohort of chronically infected subjects prior to initiation of antiretroviral therapy (ART) and individuals with suppressed viral load on ART. We show that IFN- induction in NK cells upon PBMC stimulation by HIV Ag varies inversely with viremia and depends on HIV-specific CD4 T cell help. We demonstrate in both untreated and ART-suppressed individuals that dual PD-1 and IL-10 blockade enhances cytokine secretion of NK cells via restored HIV-specific CD4 T cell function, that soluble factors contribute to these immunotherapeutic effects, and that they depend on IL-2 and IL-12 signaling. Importantly, we show that inhibition of the PD-1 and IL-10 pathways also increases NK degranulation and killing of target cells. This study demonstrates a previously underappreciated relationship between CD4 T cell impairment and NK cell exhaustion in HIV infection, provides a proof of principle that reversal of adaptive immunity exhaustion can improve the innate immune response, and suggests that immune checkpoint modulation that improves CD4/NK cell cooperation can be used as adjuvant therapy in HIV infection.

https://ift.tt/2A4JKJm

B7-H4 Modulates Regulatory CD4+ T Cell Induction and Function via Ligation of a Semaphorin 3a/Plexin A4/Neuropilin-1 Complex [IMMUNE REGULATION]

The potent immune regulatory function of an agonistic B7-H4-Ig fusion protein (B7-H4Ig) has been demonstrated in multiple experimental autoimmune models; however, the identity of a functional B7-H4 receptor remained unknown. The biological activity of B7-H4 is associated with decreased inflammatory CD4⁺ T cell responses as supported by a correlation between B7-H4–expressing tumor-associated macrophages and Foxp3⁺ T cells within the tumor microenvironment. Recent data indicate that members of the semaphorin (Sema)/plexin/neuropilin (Nrp) family of proteins both positively and negatively modulate immune cell function. In this study, we show that B7-H4 binds the soluble Sema family member Sema3a. Additionally, B7-H4Ig–induced inhibition of inflammatory CD4⁺ T cell responses is lost in both Sema3a functional mutant mice and mice lacking Nrp-1 expression in Foxp3⁺ T cells. These findings indicate that B7-H4Ig binds to Sema3a, which acts as a functional bridge to stimulate an Nrp-1/Plexin A4 heterodimer to form a functional immunoregulatory receptor complex resulting in increased levels of phosphorylated PTEN and enhanced regulatory CD4⁺ T cell number and function.

https://ift.tt/2mBzMFJ

Blocking TIR Domain Interactions in TLR9 Signaling [INNATE IMMUNITY AND INFLAMMATION]

Interaction of TLR9 with ligands activates NF-B, leading to proinflammatory cytokine production. Excessive TLR activation is a pathogenic factor for inflammatory diseases. This study has examined cell-permeating decoy peptides (CPDPs) derived from the TLR9 Toll/IL-1R resistance (TIR) domain. CPDP 9R34, which included AB loop, β-strand B, and N-terminal BB loop residues, inhibited TLR9 signaling most potently. CPDPs derived from α-helices C, D, and E (i.e., 9R6, 9R9, and 9R11) also inhibited TLR9-induced cytokines but were less potent than 9R34. 9R34 did not inhibit TLR2/1, TLR4, or TLR7 signaling. The N-terminal deletion modification of 9R34, 9R34-N, inhibited TLR9 as potently as the full length 9R34. Binding of 9R34-N to TIR domains was studied using cell-based Förster resonance energy transfer/fluorescence lifetime imaging approach. Cy3-labeled 9R34-N dose-dependently decreased fluorescence lifetime of TLR9 TIR–Cerulean (Cer) fusion protein. Cy3–9R34-N also bound TIRAP TIR, albeit with a lesser affinity, but not MyD88 TIR, whereas CPDP from the opposite TIR surface, 9R11, bound both adapters and TLR9. i.p. administration of 9R34-N suppressed oligonucleotide-induced systemic cytokines and lethality in mice. This study identifies a potent, TLR9-specific CPDP that targets both receptor dimerization and adapter recruitment. Location of TIR segments that represent inhibitory CPDPs suggests that TIR domains of TLRs and TLR adapters interact through structurally homologous surfaces within primary receptor complex, leading to formation of a double-stranded, filamentous structure. In the presence of TIRAP and MyD88, primary complex can elongate bidirectionally, from two opposite ends, whereas in TIRAP-deficient cells, elongation is unidirectional, only through the αE side.

https://ift.tt/2A4JIBe

Active mTORC2 Signaling in Naive T Cells Suppresses Bone Marrow Homing by Inhibiting CXCR4 Expression [IMMUNE REGULATION]

Recirculation of naive T cells between secondary lymphoid organs to receive survival cues and scan for signs of infection or other pathologic conditions is important for immune homeostasis and effective immune responses. Although the mechanisms that specifically guide the entry of naive T cells into secondary lymphoid organs are well studied, the mechanisms that keep them from fluxing into inappropriate or undesirable compartments, such as healthy tissues or bone marrow, are less well understood. In this study, we report an unexpected finding that under steady state, bone marrow homing of naive T cells is actively suppressed by mTORC2 signaling. We found that in mice, T cell–specific deletion of an essential mTORC2 component Sin1 results in increased accumulation of naive T cells in the bone marrow. Mechanistically, we show that loss of mTORC2 signaling in naive T cells results in enhanced FOXO1 activity, which leads to increased CXCR4 expression and chemotactic response to CXCL12, a key chemokine that promotes bone marrow homing and retention of T cells. Together, the results of our study reveal a novel role of mTORC2 in T cell homeostasis via active suppression of naive T cell bone marrow homing by the mTORC2–FOXO1–CXCR4 axis.

https://ift.tt/2uXQ7Zi

Neck stiffness in a post-irradiated nasopharyngeal carcinoma adult: An unusual diagnosis

Publication date: Available online 23 July 2018

Source: Auris Nasus Larynx

Author(s): Kang Ni Lorna Ting, Yew Toong Liew, Zulkiflee Abu Bakar, Prepageran Narayanan

Abstract

Nasopharyngeal carcinoma is a neoplasm commonly found in population of South East Asia. The mainstay of treatment is high dose irradiation. Complications from radiotherapy are not uncommon especially to those nearby structures such as vertebrae and spinal cord. A 57 year-old gentleman with nasopharyngeal carcinoma (NPC) who was treated with chemo-radiation (total of 35 fractions,70 Gy) presented to us 6 months post therapy with bilateral nasal discharge and progressive neck stiffness. Nasoendoscopy showed inflamed nasophayngeal mucosa and Computed Tomography (CT) brain and cervical spine showed retropharyngeal and anterior epidural collection with extension into atlantoaxial bone and spinal cord compression. Histopathological specimen revealed features of chronic inflammations with multiple actinomycetes colonies. Our patient suffered severe neck stiffness and loss of sensations on both upper limbs. He was treated conservatively with Halo vest and intravenous antibiotics for 8 weeks and recovered fully.

Irradiation in NPC is known to cause devastating complications to cervical spine such as osteoradionecrosis, osteomyelitis. It also renders tissues hypoxic and risk of getting rare infection like actinomycosis. This report can represent a great diagnostic and therapeutic challenge with differentials of tumor recurrence, osteoradionecrosis or osteomyelitis. Patients must be regularly followed up to look for possible cervical complications as a result from irradiation, to prevent devastating outcome or prognosis.

https://ift.tt/2LhJThD

Corrigendum to “From periodontal mechanoreceptors to chewing motor control: A systematic review” [Arch. Oral Biol. 78 (2017) 109–121]

Publication date: Available online 23 July 2018

Source: Archives of Oral Biology

Author(s): Grazia Piancino Maria, Isola Gaetano, Cannavale Rosangela, Cutroneo Giuseppina, Vermiglio Giovanna, Bracco Pietro, Pio Anastasi Giuseppe

https://ift.tt/2NAWlGg

Analysis of the audiogram shape in patients with idiopathic sudden sensorineural hearing loss using a cluster analysis

Tetsuo Watanabe, MD, PhD; Masashi Suzuki, MD, PhD

Abstract

We performed a cluster analysis to classify the audiogram shape in patients with idiopathic sudden sensorineural hearing loss (ISSNHL). We also investigated whether the audiogram shape is a prognostic indicator in the management of ISSNHL. A total of 115 inpatients with ISSNHL treated between 2001 and 2010 were analyzed. The data collected included age, sex, duration of hearing loss at the time of treatment, and the presence or absence of tinnitus, vertigo, diabetes, nystagmus, and canal paresis. A hierarchical cluster analysis was performed using the hearing threshold for each frequency on audiograms as variables. A logistic regression model was used for the prognostic analysis. The audiogram shape was classified into four clusters: (1) crossing horizontally pattern of all tones; (2) up-sloping pattern of low-tone loss; (3) deaf pattern; and (4) down-sloping pattern of high-tone loss. The age of the patient, presence of canal paresis, and audiogram shape showed statistically significant relationships with hearing improvement. The audiogram shape based on the cluster analysis demonstrated a significant relationship with hearing improvement in patients with ISSNHL. Further studies are needed to elucidate the underlying etiology of each audiogram shape.

ENT Journal provides full text articles to our registered members.
Please log in or sign up for a FREE membership to view the full content:

• REGISTER AS A MEMBER
• If you are already registered, SIGN IN

You may also like to:

• Sign Up For The Free eNewsletter

https://ift.tt/2mDdX8K

Analyzing Medicare payments to otologists

T. Edward Imbery, MD; Brian D. Nicholas, MD; Parul Goyal, MD, MBA

Abstract

The study objective was to analyze Medicare payment data to otologists compared to otolaryngologists, using the publicly released Centers for Medicare and Medicaid Services dataset. Charges, payments, and common Current Procedural Terminology codes were obtained. Otology providers were selected from the roster of the American Otological Society. Descriptive statistics and unequal variance two-tailed t tests were used for comparisons between otologists (n = 147) and otolaryngologists (n = 8,318). The mean overall submitted charge was $204,851 per otology provider and was $211,209 per other otolaryngology providers (non-otologists) (p = 0.92). The mean payment to otologists was $56,191 (range: $297 to $555,274, standard deviation [SD] ±$68,540) and significantly lower (p = 0.005) than $77,275 to otolaryngologists (range: $94 to $2,123,900, SD ±$86,423). The mean submitted charge-to-payment ratio (fee multiplier) per otology provider was 3.87 (range 1.50 to 9.10, SD ±1.70), which was significantly higher (p < 0.0001) than the ratio for otolaryngologists (mean 2.91; range: 1.25 to 17.51, SD ±1.22). Office visit evaluation and management (E&M) codes made up the majority in terms of use and payments. Interestingly, allergy-based services comprised a substantial amount of repeat use among a small subset of otologists. Audiology services were billed by a similar percentage of otologists and other otolaryngologists (52%), but otologists received a significantly higher overall payment for these services.

ENT Journal provides full text articles to our registered members.
Please log in or sign up for a FREE membership to view the full content:

• REGISTER AS A MEMBER
• If you are already registered, SIGN IN

You may also like to:

• Sign Up For The Free eNewsletter

https://ift.tt/2A0pGrJ

Ocular vestibular evoked myogenic potentials and intravestibular intralabyrinthine schwannomas

Massimo Ralli, MD, PhD; Giuseppe Nola, MD; Massimo Fusconi, MD; Luca Sparvoli, MD; Giovanni Ralli, MD

Abstract

Intravestibular intralabyrinthine schwannomas (ILSs) are uncommon benign tumors that arise from the saccular, utricular, and lateral and superior ampullary nerves. According to the literature, there is an average delay of 8 years between the onset of symptoms and diagnosis. The diagnosis is based on an audiovestibular examination and magnetic resonance imaging (MRI). We describe a case of intravestibular ILS in which we included the ocular vestibular evoked myogenic potentials (oVEMPs) test in the diagnostic workup. The oVEMPs test is a relatively new neurophysiologic diagnostic modality that evaluates the superior vestibular pathway and the ascending contralateral pathway through the vestibulo-ocular reflex. In our case, a 65-year-old man presented with progressive right-sided sensorineural hearing loss, dizziness, and tinnitus and fullness in his right ear. Audiovestibular examination and MRI detected an intravestibular ILS on the right. We found that oVEMPs were absent on the contralateral side, which contributed to the diagnostic process. The detection of oVEMPs can provide detailed information on the functionality of the macula of the utricle and the lateral and superior ampullary nerves, with a precise identification of the affected area. Based on our findings, we discuss the role of oVEMPs in the diagnosis of an intravestibular ILS.

ENT Journal provides full text articles to our registered members.
Please log in or sign up for a FREE membership to view the full content:

• REGISTER AS A MEMBER
• If you are already registered, SIGN IN

You may also like to:

• Sign Up For The Free eNewsletter

https://ift.tt/2mBNfxi

Warthin tumor of the larynx: A case report and review of the literature

Irit Duek, MD; Miki Paker, MD; Ziv Gil, MD, PhD; Jacob T. Cohen, MD

Abstract

Warthin tumor (papillary cystadenoma lymphomatosum) is a benign salivary gland tumor that occurs almost exclusively in the parotid gland. As far as we know, only 15 cases of laryngeal Warthin tumor have been previously reported worldwide. We describe the case of a 75-year-old woman with a supraglottic tumor that mimicked a mucoepidermoid carcinoma. The tumor was completely excised via a transcervical approach. Pathology identified it as a Warthin tumor. At follow-up, the patient maintained good oral intake. Computed tomography 3 months postoperatively confirmed complete tumor resection and detected no evidence of residual disease or recurrence. We also discuss our review of the literature on benign laryngeal salivary gland tumors, which included an analysis of 112 cases. The most common tumors were oncocytic cystadenomas (n = 65), pleomorphic adenomas (n = 28), and Warthin tumors (n = 15); we also found 2 cases each of basal cell adenomas and myoepitheliomas. The most common single tumor site was the glottis (n = 25), followed by the supraglottis (n = 24), and the subglottis (n = 22); 5 cases occurred in multiple sites, and the specific site was not reported in 36 cases. Benign laryngeal neoplasms of salivary gland origin should be carefully evaluated. Distinguishing these tumors from malignant lesions and establishing the correct diagnosis are crucial for treatment planning. Large lesions with extralaryngeal extension can be resected completely via an open external approach.

ENT Journal provides full text articles to our registered members.
Please log in or sign up for a FREE membership to view the full content:

• REGISTER AS A MEMBER
• If you are already registered, SIGN IN

You may also like to:

• Sign Up For The Free eNewsletter

https://ift.tt/2A0petx

Endoscopic view of a sinonasal osteoma

Dewey A. Christmas, MD; Joseph P. Mirante, MD, MBA, FACS; Eiji Yanagisawa, MD, FACS

Surgical intervention is indicated only in the event of symptoms or complications caused by the osteoma.

ENT Journal provides full text articles to our registered members.
Please log in or sign up for a FREE membership to view the full content:

• REGISTER AS A MEMBER
• If you are already registered, SIGN IN

You may also like to:

• Sign Up For The Free eNewsletter

https://ift.tt/2mALlgl

Inflammatory myofibroblastic tumor of the larynx

Yu-Hsuan Wang, MD; Yi-Shing Leu, MD; Wei-Chin Chang, MD

Inflammatory myofibroblastic tumor usually involves the lungs, bronchopulmonary tree, and abdominal viscera.

ENT Journal provides full text articles to our registered members.
Please log in or sign up for a FREE membership to view the full content:

• REGISTER AS A MEMBER
• If you are already registered, SIGN IN

You may also like to:

• Sign Up For The Free eNewsletter

https://ift.tt/2A44D7u

Accessory submandibular duct sialolithiasis identified during sialendoscopy

Andrew J. Thomas, MD; Kevin F. Wilson, MD

Abstract

We describe a unique case of a 62-year-old patient with recurrent right submandibular sialadenitis. He initially appeared to have extensive sialolithiasis of the right submandibular duct on computed tomography imaging and examination, but sialendoscopy demonstrated a normal-appearing right submandibular duct. An accessory duct posterior and parallel to the normal duct was identified at the time of sialendoscopy and was found to have extensive sialolithiasis, which required removal by both an endoscopic and intraoral technique. To the best of our knowledge, this is the first report of sialolithiasis of an accessory submandibular duct identified at the time of sialendoscopy; the other few reported cases in the literature are based primarily on findings from traditional sialography or magnetic resonance sialography. Identification of accessory salivary ducts requires intraoperative consideration of this entity during sialendoscopy. Open approaches to sialolithiasis, however, may be aided by appropriate preoperative imaging.

ENT Journal provides full text articles to our registered members.
Please log in or sign up for a FREE membership to view the full content:

• REGISTER AS A MEMBER
• If you are already registered, SIGN IN

You may also like to:

• Sign Up For The Free eNewsletter

https://ift.tt/2mFLu21

Esophageal perforation as a complication of the Heimlich maneuver in a pediatric patient: A case report

Shira L. Koss, MD; William E. Karle, MD; Gregory Dibelius, MD; Ameet Kamat, MD; Craig Berzofsky, MD

Abstract

We report a case of cervical esophageal perforation caused by the Heimlich maneuver in a healthy 16-year-old boy. The patient reported a short coughing episode while eating rice, and his mother performed the Heimlich maneuver on him. Five days later, he presented to the emergency department with throat pain, odynophagia, secretion intolerance, muffled voice, and neck stiffness. He was admitted to the pediatric intensive care unit for conservative management. The next day he underwent transcervical incision and drainage of purulence, but the esophageal perforation could not be visualized at that time. The perforation was identified several days later and successfully repaired surgically. Esophageal perforation as a complication of the Heimlich maneuver is exceedingly rare, but the clinician should be aware of this entity in the differential diagnosis, as it is associated with a high mortality rate and warrants multidisciplinary care, including timely surgical intervention.

ENT Journal provides full text articles to our registered members.
Please log in or sign up for a FREE membership to view the full content:

• REGISTER AS A MEMBER
• If you are already registered, SIGN IN

You may also like to:

• Sign Up For The Free eNewsletter

https://ift.tt/2uSFgjc

HPV-related sinonasal carcinoma with adenoid cystic-like features with intracranial invasion

Yuntsung Hung, MD; Yu-Yen Chung, MD; Mei-Ling Chen, MD; Jyun-Ying Guo, MD

HPV-related sinonasal carcinoma with adenoid cystic-like features is a recently described tumor with less than 10 cases reported in the literature to date.

ENT Journal provides full text articles to our registered members.
Please log in or sign up for a FREE membership to view the full content:

• REGISTER AS A MEMBER
• If you are already registered, SIGN IN

You may also like to:

• Sign Up For The Free eNewsletter

https://ift.tt/2LkcS4E

Tympanometric volume as a useful tool for the evaluation of middle ear status in chronic otitis media

Shin Hye Kim, MD, PhD; Hyun Sook Hong, MD, PhD; Jong Dae Lee, MD, PhD; Moo Kyun Park, MD, PhD

Abstract

Tympanometric volume is a useful tool for evaluating middle ear status in otitis media. However, its usefulness in chronic otitis media (COM) has not been well evaluated. This study aimed to investigate whether tympanometric volume reflects the status of the middle ear and mastoid or can provide clinical information about patients with COM and subsequent tympanic membrane perforation. A prospective cohort study including 50 adult patients with COM and subsequent tympanic membrane perforation was performed. The volumes of the middle ear and mastoid were preoperatively calculated using tympanometry and three- dimensional computed tomography (CT) reconstruction of the temporal bone, respectively. During surgery for COM, the patency of the middle ear and mastoid antrum was evaluated. The volumes of the middle ear and mastoid measured by tympanometry and CT were compared with the surgical findings. When the mastoid antrum was patent, the volumes of the middle ear and mastoid measured by tympanometry and CT were well correlated. Moreover, the difference in the volumes measured by tympanometry between the affected and unaffected ears was large. However, when the mastoid antrum was poorly aerated, the difference in the volumes measured by tympanometry between the affected and unaffected ears was small. Middle ear status can be evaluated according to the difference in tympanometric volume between the two ears. If the tympanometric volume suggests poor aeration of the middle ear and mastoid, clinicians should consider procedures for mastoid aeration.

ENT Journal provides full text articles to our registered members.
Please log in or sign up for a FREE membership to view the full content:

• REGISTER AS A MEMBER
• If you are already registered, SIGN IN

You may also like to:

• Sign Up For The Free eNewsletter

https://ift.tt/2LHACvN

Prevalence of food allergy in Vietnam: comparison of web-based with traditional paper-based survey

Web-based surveys (WBS) are increasingly applied in epidemiological studies as an appealing alternative to traditional survey methods. Rapid data collection, reduced expenditure and ease of access to large pop...

https://ift.tt/2NFsblh

Message from the Center for Global Health's Interim Director

Center for Global Interim Director, Dr. Robert Croyle, discusses CGH accomplishments and plans for the new leadership.

https://ift.tt/2NDyfKG

Rural-urban disparities in time to diagnosis and treatment for colorectal and breast cancer

Bergin, RJ; Emery, J; Bollard, RC; Falborg, AZ; Jensen, H; Weller, D; Menon, U; ... White, V; + view all Bergin, RJ; Emery, J; Bollard, RC; Falborg, AZ; Jensen, H; Weller, D; Menon, U; Vedsted, P; Thomas, RJ; Whitfield, K; White, V; - view fewer (2018) Rural-urban disparities in time to diagnosis and treatment for colorectal and breast cancer. Cancer Epidemiology, Biomarkers & Prevention 10.1158/1055-9965.EPI-18-0210 . (In press).

https://ift.tt/2LfIoAK

The case for biophysics super-groups in physics departments

Hoogenboom, BW; Leake, MC; (2018) The case for biophysics super-groups in physics departments. Physical Biology , 15 (6) , Article 060201. 10.1088/1478-3975/aaca0a . Green open access

https://ift.tt/2LGJzFD

Efficient visible light-driven water oxidation and proton reduction by an ordered covalent triazine-based framework

Xie, J; Shevlin, SA; Ruan, Q; Moniz, SJA; Liu, Y; Liu, X; Li, Y; ... Tang, J; + view all Xie, J; Shevlin, SA; Ruan, Q; Moniz, SJA; Liu, Y; Liu, X; Li, Y; Lau, CC; Guo, ZX; Tang, J; - view fewer (2018) Efficient visible light-driven water oxidation and proton reduction by an ordered covalent triazine-based framework. Energy and Environmental Science , 11 (6) pp. 1617-1624. 10.1039/c7ee02981k . Green open access

https://ift.tt/2LfXcPZ

Energy use and height in office buildings

Godoy-Shimizu, D; Steadman, P; Hamilton, I; Donn, M; Evans, S; Moreno, G; Shayesteh, H; (2018) Energy use and height in office buildings. Building Research and Information 10.1080/09613218.2018.1479927 . (In press). Green open access

https://ift.tt/2JNDjdi

Predicting intolerance of uncertainty in individuals with eating disorder symptoms

Sternheim, LC; Fisher, M; Harrison, A; Watling, R; (2017) Predicting intolerance of uncertainty in individuals with eating disorder symptoms. Journal of Eating Disorders , 5 (1) 10.1186/s40337-017-0152-4 . Green open access

https://ift.tt/2LdGYGO

Soundscape mapping in environmental noise management and urban planning: Case studies in two UK cities

Margaritis, E; Kang, J; (2017) Soundscape mapping in environmental noise management and urban planning: Case studies in two UK cities. Noise Mapping , 4 (1) pp. 87-103. 10.1515/noise-2017-0007 . Green open access

https://ift.tt/2JNCyRu

Predictive model for the scale-out of small channel two-phase flow contactors

Garciadiego Ortega, E; Tsaoulidis, D; Angeli, P; (2018) Predictive model for the scale-out of small channel two-phase flow contactors. Chemical Engineering Journal , 351 pp. 589-602. 10.1016/j.cej.2018.06.020 . (In press). Green open access

https://ift.tt/2LdGTmu

Robust Energy Harvesting FD Transmission: Interference Suppression vs Exploitation

Kabir, MT; Khandaker, MRA; Masouros, C; (2018) Robust Energy Harvesting FD Transmission: Interference Suppression vs Exploitation. IEEE Communications Letters 10.1109/LCOMM.2018.2848929 . (In press). Green open access

https://ift.tt/2LHelhF

Risks of ovarian, breast, and corpus uteri cancer in women treated with assisted reproductive technology in Great Britain, 1991-2010: data linkage study including 2.2 million person years of observation.

Williams, CL; Jones, ME; Swerdlow, AJ; Botting, BJ; Davies, MC; Jacobs, I; Bunch, KJ; ... Sutcliffe, AG; + view all Williams, CL; Jones, ME; Swerdlow, AJ; Botting, BJ; Davies, MC; Jacobs, I; Bunch, KJ; Murphy, MFG; Sutcliffe, AG; - view fewer (2018) Risks of ovarian, breast, and corpus uteri cancer in women treated with assisted reproductive technology in Great Britain, 1991-2010: data linkage study including 2.2 million person years of observation. BMJ , 362 , Article k2644. 10.1136/bmj.k2644 . Green open access

https://ift.tt/2Lkl4C5

Plasminogen activation triggers transthyretin amyloidogenesis in vitro

Mangione, PP; Verona, G; Corazza, A; Marcoux, J; Canetti, D; Giorgetti, S; Raimondi, S; ... Bellotti, V; + view all Mangione, PP; Verona, G; Corazza, A; Marcoux, J; Canetti, D; Giorgetti, S; Raimondi, S; Stoppini, M; Esposito, M; Relini, A; Canale, C; Valli, M; Marchese, L; Faravelli, G; Obici, L; Hawkins, PN; Taylor, GW; Gillmore, JD; Pepys, MB; Bellotti, V; - view fewer (2018) Plasminogen activation triggers transthyretin amyloidogenesis in vitro. Journal of Biological Chemistry 10.1074/jbc.RA118.003990 . (In press). Green open access

https://ift.tt/2JNTCXx

Boosting heterojunction interaction in electrochemical construction of MoS2 quantum dots@TiO2 nanotube arrays for highly effective photoelectrochemical performance and electrocatalytic hydrogen evolution

Dong, J; Zhang, X; Huang, J; Gao, S; Mao, J; Cai, J; Chen, Z; ... Lai, Y; + view all Dong, J; Zhang, X; Huang, J; Gao, S; Mao, J; Cai, J; Chen, Z; Sathasivam, S; Carmalt, CJ; Lai, Y; - view fewer (2018) Boosting heterojunction interaction in electrochemical construction of MoS2 quantum dots@TiO2 nanotube arrays for highly effective photoelectrochemical performance and electrocatalytic hydrogen evolution. Electrochemistry Communications , 93 pp. 152-157. 10.1016/j.elecom.2018.07.008 . (In press).

https://ift.tt/2LdGzEi

Early and Highly Suppressive ART are Main Factors Associated with Low Viral Reservoir in European Perinatally HIV Infected Children

Tagarro, A; Chan, M; Zangari, P; Ferns, B; Foster, C; De Rossi, A; Nastouli, E; ... EPIICAL Consortium, ; + view all Tagarro, A; Chan, M; Zangari, P; Ferns, B; Foster, C; De Rossi, A; Nastouli, E; Muñoz-Fernández, MA; Gibb, D; Rossi, P; Giaquinto, C; Babiker, A; Fortuny, C; Freguja, R; Cotugno, N; Judd, A; Noguera-Julian, A; Navarro, ML; Mellado, MJ; Klein, N; Palma, P; Rojo, P; EPIICAL Consortium, ; - view fewer (2018) Early and Highly Suppressive ART are Main Factors Associated with Low Viral Reservoir in European Perinatally HIV Infected Children. Journal of Acquired Immune Deficiency Syndromes (JAIDS) 10.1097/QAI.0000000000001789 . (In press).

https://ift.tt/2JNBKMs

Gate Oxide Electrical Stability of p-type Diamond MOS Capacitors

Loto, O; Florentin, M; Masante, C; Donato, N; Hicks, ML; Pakpour-Tabrizi, AC; Jackman, RB; ... Gheeraert, E; + view all Loto, O; Florentin, M; Masante, C; Donato, N; Hicks, ML; Pakpour-Tabrizi, AC; Jackman, RB; Zuerbig, V; Godignon, P; Eon, D; Pernot, J; Udrea, F; Gheeraert, E; - view fewer (2018) Gate Oxide Electrical Stability of p-type Diamond MOS Capacitors. IEEE Transactions on Electron Devices , 65 (8) pp. 3361-3364. 10.1109/TED.2018.2847340 . Green open access

https://ift.tt/2Lj9EOC

EANM-EAN recommendations for the use of brain 18 F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) in neurodegenerative cognitive impairment and dementia: Delphi consensus

Nobili, F; Arbizu, J; Bouwman, F; Drzezga, A; Agosta, F; Nestor, P; Walker, Z; ... EANM-EAN Task Force for the Prescription of FDG-PET for Dementin, ; + view all Nobili, F; Arbizu, J; Bouwman, F; Drzezga, A; Agosta, F; Nestor, P; Walker, Z; Boccardi, M; EANM-EAN Task Force for the Prescription of FDG-PET for Dementin, ; - view fewer (2018) EANM-EAN recommendations for the use of brain 18 F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) in neurodegenerative cognitive impairment and dementia: Delphi consensus. European Journal of Neurology 10.1111/ene.13728 . (In press).

https://ift.tt/2LHXVW7

Preface

Zlatanova, S; Laurini, R; Baucic, M; Rumor, M; Ellul, C; Coors, V; (2016) Preface. In: ISPRS Annals of the Photogrammetry, Remote Sensing and Spatial Information Sciences. (pp. p. 1). International Society for Photogrammetry and Remote Sensing: Split, Croatia. Green open access

https://ift.tt/2JMDJAB

Cohort profile: prescriptions dispensed in the community linked to the national cancer registry in England

Henson, KE; Brock, R; Shand, B; Coupland, VH; Elliss-Brookes, L; Lyratzopoulos, G; Godfrey, P; ... Rashbass, J; + view all Henson, KE; Brock, R; Shand, B; Coupland, VH; Elliss-Brookes, L; Lyratzopoulos, G; Godfrey, P; Haigh, A; Hunter, K; McCabe, MG; Mitchell, G; Monckton, N; Robson, R; Round, T; Wong, K; Rashbass, J; - view fewer (2018) Cohort profile: prescriptions dispensed in the community linked to the national cancer registry in England. BMJ Open , 8 (7) , Article e020980. 10.1136/bmjopen-2017-020980 . Green open access

https://ift.tt/2LjXpBC

The problem with composite indicators

Barclay, M; Dixon-Woods, M; Lyratzopoulos, G; (2019) The problem with composite indicators. BMJ Quality and Safety (In press).

https://ift.tt/2LHhP3v

Throughput optimization for admitting NFV-enabled requests in cloud networks

Xu, Z; Liang, W; Galis, A; Ma, Y; Xia, Q; Xu, W; (2018) Throughput optimization for admitting NFV-enabled requests in cloud networks. Computer Networks , 143 pp. 15-29. 10.1016/j.comnet.2018.06.015 . (In press).

https://ift.tt/2LdG6C2

Expert consensus guidelines for the genetic diagnosis of Alport syndrome

Savige, J; Ariani, F; Mari, F; Bruttini, M; Renieri, A; Gross, O; Deltas, C; ... Storey, H; + view all Savige, J; Ariani, F; Mari, F; Bruttini, M; Renieri, A; Gross, O; Deltas, C; Flinter, F; Ding, J; Gale, DP; Nagel, M; Yau, M; Shagam, L; Torra, R; Ars, E; Hoefele, J; Garosi, G; Storey, H; - view fewer (2018) Expert consensus guidelines for the genetic diagnosis of Alport syndrome. Pediatric Nephrology 10.1007/s00467-018-3985-4 . (In press).

https://ift.tt/2JN2vR8

Comparative genomics of Campylobacter concisus: Analysis of clinical strains reveals genome diversity and pathogenic potential

Gemmell, MR; Berry, S; Mukhopadhya, I; Hansen, R; Nielsen, HL; Bajaj-Elliott, M; Nielsen, H; Gemmell, MR; Berry, S; Mukhopadhya, I; Hansen, R; Nielsen, HL; Bajaj-Elliott, M; Nielsen, H; Hold, GL; - view fewer (2018) Comparative genomics of Campylobacter concisus: Analysis of clinical strains reveals genome diversity and pathogenic potential. Emerging Microbes & Infections , 7 , Article 116. 10.1038/s41426-018-0118-x . Green open access

https://ift.tt/2LjGUFx

The Detection of Barrett's Esophagus by Gastrointestinal Endoscopy Prevents Esophageal Carcinoma in Morbid Obese After Sleeve Gastrectomy

Condition:   Gastroesophageal Reflux
Intervention:  
Sponsor:   Centre Hospitalier Universitaire de Nice
Recruiting

https://ift.tt/2uZGmtq

Nomograms to Precisely Predict Conditional Risk of Recurrence for Patients With Laryngeal Cancer

Condition:   Recurrent Laryngeal Cancer
Intervention:   Other: Recurrence laryngeal cancer
Sponsor:   First Affiliated Hospital, Sun Yat-Sen University
Recruiting

https://ift.tt/2LCnN9i

Giftschlangen in Deutschland und Europa

Zusammenfassung

Schätzungen gehen von weltweit mehr als 5.000.000 Schlangenbissen pro Jahr aus; 2.500.000 von diesen führen zu Vergiftungserscheinungen, knapp 400.000 hinterlassen dauerhafte Folgen, und ca. 125.000 verlaufen tödlich. In Deutschland gibt es nur 2 Giftschlangen, die Kreuzotter und die Aspisviper. Bisse durch giftige Schlangen sind aber nicht nur in Deutschland, sondern auch auf dem gesamten Gebiet des geografischen Europa bis zum Beweis des Gegenteils stets als bedrohlicher Notfall einzuordnen. Jeder dieser Bisse sollte, selbst bei fehlender Symptomatik, für mindestens 24 Stunden überwacht werden, möglichst in einer mit der medizinischen Versorgung von Schlangenbissen vertrauten Einrichtung. Reisenden sollte dringend geraten werden, sich vor Reiseantritt über das am Reiseziel übliche Aufkommen giftiger Schlangen zu informieren

https://ift.tt/2zYQM2e

Ex vivo expanded tumour-infiltrating lymphocytes from ovarian cancer patients release anti-tumour cytokines in response to autologous primary ovarian cancer cells

Abstract

Epithelial ovarian cancer (EOC) is the leading cause of gynaecological cancer-related death in Europe. Although most patients achieve an initial complete response with first-line treatment, recurrence occurs in more than 80% of cases. Thus, there is a clear unmet need for novel second-line treatments. EOC is frequently infiltrated with T lymphocytes, the presence of which has been shown to be associated with improved clinical outcomes. Adoptive T-cell therapy (ACT) using ex vivo-expanded tumour-infiltrating lymphocytes (TILs) has shown remarkable efficacy in other immunogenic tumours, and may represent a promising therapeutic strategy for EOC. In this preclinical study, we investigated the efficacy of using anti-CD3/anti-CD28 magnetic beads and IL-2 to expand TILs from freshly resected ovarian tumours. TILs were expanded for up to 3 weeks, and then subjected to a rapid-expansion protocol (REP) using irradiated feeder cells. Tumours were collected from 45 patients with EOC and TILs were successfully expanded from 89.7% of biopsies. Expanded CD4⁺ and CD8⁺ subsets demonstrated features associated with memory phenotypes, and had significantly higher expression of key activation and functional markers than unexpanded TILs. Expanded TILs produced anti-tumour cytokines when co-cultured with autologous tumour cells, inferring tumour cytotoxicity. Our findings demonstrate that it is possible to re-activate and expand tumour-reactive T cells from ovarian tumours. This presents a promising immunotherapy that could be used sequentially or in combination with current therapeutic strategies.

https://ift.tt/2uVFu9b

Timothy O. Benson and Eva Forgacs, eds., Between Worlds: A Sourcebook of Central European Avant-Gardes, AND Central European Avant-Garedes: Exchange and Transformation, 1910-1930

Zusi, PA; (2005) Timothy O. Benson and Eva Forgacs, eds., Between Worlds: A Sourcebook of Central European Avant-Gardes, AND Central European Avant-Garedes: Exchange and Transformation, 1910-1930. [Review]. Slavic and East European Journal , 49 (2) pp. 331-332. 10.2307/20058281 .

https://ift.tt/2LidF67

Vladimír Birgus and Jan Mlčoch, eds. Jaroslav Rössler: Czech Avant-Garde Photographer

Zusi, PA; (2004) Vladimír Birgus and Jan Mlčoch, eds. Jaroslav Rössler: Czech Avant-Garde Photographer. [Review]. Slavic and East European Journal , 48 (4) pp. 698-699.

https://ift.tt/2JLdL0x

Karel Teige, The Minimum Dwelling, ed. and trans. Eric Dluhosch

Zusi, PA; (2004) Karel Teige, The Minimum Dwelling, ed. and trans. Eric Dluhosch. [Review]. Slavic and East European Journal , 48 (1) pp. 135-136.

https://ift.tt/2LkSArS

Design of HIFU treatment plans using an evolutionary strategy

Cudova, M; Treeby, BE; Jaros, J; (2018) Design of HIFU treatment plans using an evolutionary strategy. In: Aguirre, HE and Takadama, K, (eds.) Proceedings of the Genetic and Evolutionary Computation Conference Companion. (pp. pp. 1568-1575). ACM: New York, NY, USA. Green open access

https://ift.tt/2JMXRTr

Fifth International Space Syntax Symposium, Delft, The Netherlands, 13-17 June 2005

Vaughan, L; (2005) Fifth International Space Syntax Symposium, Delft, The Netherlands, 13-17 June 2005. Urban Morphology , 9 (2) pp. 81-82.

https://ift.tt/2LiM0BQ

Developing Ecologically Sustainable Education for Singapore Preschool Children

Ang, L; Chua, HL; (2010) Developing Ecologically Sustainable Education for Singapore Preschool Children. Action Research Today in Early Childhood (ARTEC). Special Issue , 1 (1) pp. 45-52.

https://ift.tt/2JMXI2l

Lone Actor Terrorists: A Residence-to-Crime Approach

Marchment, Z; Bouhana, N; Gill, P; (2018) Lone Actor Terrorists: A Residence-to-Crime Approach. Terrorism and Political Violence 10.1080/09546553.2018.1481050 . (In press).

https://ift.tt/2LiM9oS

An introduction to digital PET-CT Introduction aux cameras TEP-TDM digitales

Hutton, BF; (2018) An introduction to digital PET-CT Introduction aux cameras TEP-TDM digitales. Médecine Nucléaire , 42 (3) pp. 196-197. 10.1016/j.mednuc.2018.03.134 .

https://ift.tt/2JN9wkP

Differences between women's and men's socioeconomic inequalities in health: longitudinal analysis of the Canadian population, 1994-2003

Luchenski, S; Quesnel-Vallee, A; Lynch, J; (2008) Differences between women's and men's socioeconomic inequalities in health: longitudinal analysis of the Canadian population, 1994-2003. Journal of Epidemiology & Community Health , 62 (12) pp. 1036-1044. 10.1136/jech.2007.068908 . Green open access

https://ift.tt/2LfXqXk

Special issue: Preparing to teach mathematics pathways beyond 16

Smith, C; Golding, J; Bretscher, N; (2018) Special issue: Preparing to teach mathematics pathways beyond 16. Teaching Mathematics and its Applications: An International Journal of the IMA , 37 (2) pp. 53-54. 10.1093/teamat/hry011 .

https://ift.tt/2LDcHNT

Primary Nasopharyngeal Kaposi Sarcoma as Index Diagnosis of AIDS in a Previously Healthy Man

Abstract

A 38-year-old, previously healthy man presented with blood-stained saliva and epistaxis. A 3 mm nasopharyngeal lesion was found. A biopsy was performed and microscopic examination revealed a Kaposi sarcoma. The patient was subsequently found to be positive for human immunodeficiency virus (HIV). The diagnosis of Kaposi sarcoma in the presence of HIV infection advanced his disease to Acquired Immunodeficiency Syndrome (AIDS). Primary manifestation of Kaposi sarcoma in the nasopharynx is extremely rare. The histologic differential diagnosis of Kaposi sarcoma in this unusual site, especially without the clinical history of immunosuppression, is broad. Awareness that nasopharynx can be a primary involvement site of Kaposi sarcoma and serves as index diagnosis of AIDS is important given its serious clinical implication.

https://ift.tt/2JMawpm

ASCO – vom amerikanischen Krebskongress 2018

https://ift.tt/2uXFXb7

Leveraging Quality Improvement and Patient Safety Initiatives to Enhance Value and Patient-Centered Care in Otolaryngology

Abstract

Purpose of Review

Patient safety and quality improvement (PS/QI) initiatives have rapidly proliferated through all fields of healthcare including otolaryngology. Harnessing these initiatives provides an opportunity to systematically evaluate and disseminate best practices and to evaluate their effect in improving value for patients.

Recent Findings

New data registries and disease-specific quality improvement collaboratives provide opportunities for otolaryngologists to use data to enhance quality. We describe PS/QI measures that enhance value by improving quality and controlling costs. These include data registries that allow "big data" approaches, the benefits of multidisciplinary teams and care coordination, subspecialty-specific initiatives, use of M&M conference as a launchpad for PS/QI activity, and barriers to implementation of PS/QI strategies.

Summary

As changes in healthcare continue to accelerate, otolaryngologists who embrace opportunities to optimize value in their respective subspecialties will see improved outcomes for their patients and will reap the benefits of thriving, fulfilling clinical practices.

https://ift.tt/2Ab4tvl

Primary Nasopharyngeal Kaposi Sarcoma as Index Diagnosis of AIDS in a Previously Healthy Man

Abstract

A 38-year-old, previously healthy man presented with blood-stained saliva and epistaxis. A 3 mm nasopharyngeal lesion was found. A biopsy was performed and microscopic examination revealed a Kaposi sarcoma. The patient was subsequently found to be positive for human immunodeficiency virus (HIV). The diagnosis of Kaposi sarcoma in the presence of HIV infection advanced his disease to Acquired Immunodeficiency Syndrome (AIDS). Primary manifestation of Kaposi sarcoma in the nasopharynx is extremely rare. The histologic differential diagnosis of Kaposi sarcoma in this unusual site, especially without the clinical history of immunosuppression, is broad. Awareness that nasopharynx can be a primary involvement site of Kaposi sarcoma and serves as index diagnosis of AIDS is important given its serious clinical implication.

https://ift.tt/2JMawpm

Primary Nasopharyngeal Kaposi Sarcoma as Index Diagnosis of AIDS in a Previously Healthy Man

Abstract

A 38-year-old, previously healthy man presented with blood-stained saliva and epistaxis. A 3 mm nasopharyngeal lesion was found. A biopsy was performed and microscopic examination revealed a Kaposi sarcoma. The patient was subsequently found to be positive for human immunodeficiency virus (HIV). The diagnosis of Kaposi sarcoma in the presence of HIV infection advanced his disease to Acquired Immunodeficiency Syndrome (AIDS). Primary manifestation of Kaposi sarcoma in the nasopharynx is extremely rare. The histologic differential diagnosis of Kaposi sarcoma in this unusual site, especially without the clinical history of immunosuppression, is broad. Awareness that nasopharynx can be a primary involvement site of Kaposi sarcoma and serves as index diagnosis of AIDS is important given its serious clinical implication.

https://ift.tt/2JMawpm

Circumflex retroesophageal right aortic arch: rare differential of mediastinal widening

Description 

A 48-year-old man presented to the outpatient department with complaints of inspiratory stridor and occasional dysphagia. Chest radiograph revealed bilateral symmetric widening of the superior mediastinum at the level of aortic arch with the descending aorta seen to the left of spine. No lateral displacement of tracheal air column was noted (figure 1A). The patient was referred to us for a CT angiography (CTA) with a provisional diagnosis of an aneurysm or a mediastinal mass. Review of CTA images revealed a right-sided aortic arch crossing the midline posterior to the trachea and the oesophagus in the upper mediastinum and further descending on the left side of spine (figure 1B–E). A Kommerell's diverticulum arising from the anterosuperior aspect of aorta, on the left side, gave rise to an aberrant left subclavian artery (LSCA). The circumflex arch was ectatic and measured 37 mm in its maximum...

https://ift.tt/2LDNjYd

Fixation of femoral attachment: anterior cruciate ligament avulsion fracture with arthroscopy suture loop technique

Anterior cruciate ligament (ACL) avulsion fracture is rare and mostly occur in tibial attachment. Avulsion fracture of femoral attachment of ACL was uncommon and mostly reported in skeletally immature patient. This article aims to report an interesting case of femoral attachment–ACL avulsion fracture in skeletally mature patient with arthroscopic suture loop fixation.

A 32-year-old man, with no significant medical-surgical history, sustained a right non-contact pivoting knee injury during soccer competition. Plain radiographs of knee joint demonstrated intra-articular bone fragment in the intercondylar notch space. The MRI confirmed femoral attachment–ACL avulsion fracture. Then, we planned to perform fixation of femoral attachment–ACL avulsion fracture with arthroscopy suture loop technique. At 5 months after surgery, patient had no pain and swelling knee. The physical examination demonstrated negative Lachman test, anterior drawer test, pivot shift test and patient can return to preinjury daily activity and sport activities.

https://ift.tt/2uIMl6H

Laryngopyocoele in an adult female mimicking an infected branchial cyst

The incidence of laryngopyocoele is very unusual and only 41 cases have been documented in the world literature. Although hoarseness and stridor are the predominant symptoms associated with laryngocoele,patient can present with a recurrent neck abscess misleading to an infected branchial cyst. Complete excision of the cyst can be effectively achieved by the transcervical approach, especially in case of a large lateral cyst in a stable patient.

https://ift.tt/2LFlnDu

Pericardial calcification: an uncommon presentation of rheumatic heart disease

Description 

A 42-year-old man presented to cardiology outpatient department with complaints of gradually progressive dyspnoea on exertion, easy fatigability and mild intermittent atypical chest pain for the past 9 months. Chest radiograph revealed mild cardiomegaly, enlarged left atrium and presence of multiple focal calcific specks along right inferior and upper left cardiac border (figure 1A). Transthoracic echocardiography showed thickened mitral valve leaflets with restricted mobility of posterior leaflet and mitral stenosis with mitral regurgitation.

Figure 1

Frontal chest radiograph (A) shows cardiomegaly with enlarged left atrium along with linear calcific foci (black arrows) along cardiac borders, which were confirmed to be involving the pericardium (white arrows) on coronal reconstructed maximum intensity projection images of CT angiography (B, C). Short-axis (D) and long-axis (E) reconstructions reveal thickening of mitral valve (MV) leaflets along with speck of calcification involving the anterior MV leaflet (dotted black arrow) along with...

https://ift.tt/2uIMjM7