Thermal Ablation for Treating Tumor-induced Osteomalacia in a Patient With IV Phosphate Dependency

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome associated with tumors secreting fibroblast growth factor 23 that can be cured with complete surgical resection of the tumor. However, when these tumors are at difficult locations, less invasive modalities such as thermal ablation (TA) might be a good alternative. A 40-year-old woman was seen for a second opinion because of severe hypophosphatemia with complaints of fatigue, myalgia, and muscle weakness for which she needed IV phosphate for 15 to 18 hours per day in addition to oral alfacalcidol and phosphate. Initial laboratory results revealed hypophosphatemia (0.59 mmol/L [1.83 mg/dL]; reference range, 0.90-1.50 mmol/L [8.40-10.2 mg/dL]), increased fibroblast growth factor 23 levels (137 RU/mL; reference range, &lt;125 RU/mL), and a reduced TmP-GFR (0.47 mmol/L; reference range, 0.8-1.4 mmol/L). Gallium-positron emission tomography/computed tomography (CT) showed moderately increased uptake at thoracic vertebra (Th) 8 and mildly increased uptake at Th7, suggestive of TIO. Complete tumor removal would have required resection of at least 1 vertebral body. Therefore, CT-guided TA was performed at Th8. No complications were observed, and in the months after, treatment with IV phosphate could be discontinued, indicating a satisfying result from the procedure. This extreme TIO case demonstrates that CT-guided TA can be an alternative to extensive or risky classical surgery.</p

The effect of tertiary surveys on missed injuries in trauma:A systematic review

BACKGROUND: Trauma tertiary surveys (TTS) are advocated to reduce the rate of missed injuries in hospitalized trauma patients. Moreover, the missed injury rate can be a quality indicator of trauma care performance. Current variation of the definition of missed injury restricts interpretation of the effect of the TTS and limits the use of missed injury for benchmarking. Only a few studies have specifically assessed the effect of the TTS on missed injury. We aimed to systematically appraise these studies using outcomes of two common definitions of missed injury rates and long-term health outcomes. METHODS: A systematic review was performed. An electronic search (without language or publication restrictions) of the Cochrane Library, Medline and Ovid was used to identify studies assessing TTS with short-term measures of missed injuries and long-term health outcomes. ‘Missed injury’ was defined as either: Type I) any injury missed at primary and secondary survey and detected by the TTS; or Type II) any injury missed at primary and secondary survey and missed by the TTS, detected during hospital stay. Two authors independently selected studies. Risk of bias for observational studies was assessed using the Newcastle-Ottawa scale. RESULTS: Ten observational studies met our inclusion criteria. None was randomized and none reported long-term health outcomes. Their risk of bias varied considerably. Nine studies assessed Type I missed injury and found an overall rate of 4.3%. A single study reported Type II missed injury with a rate of 1.5%. Three studies reported outcome data on missed injuries for both control and intervention cohorts, with two reporting an increase in Type I missed injuries (3% vs. 7%, P<0.01), and one a decrease in Type II missed injuries (2.4% vs. 1.5%, P=0.01). CONCLUSIONS: Overall Type I and Type II missed injury rates were 4.3% and 1.5%. Routine TTS performance increased Type I and reduced Type II missed injuries. However, evidence is sub-optimal: few observational studies, non-uniform outcome definitions and moderate risk of bias. Future studies should address these issues to allow for the use of missed injury rate as a quality indicator for trauma care performance and benchmarking

Increase in ECHOvirus 6 infections associated with neurological symptoms in the Netherlands, June to August 2016

The Dutch virus-typing network VIRO-TypeNed reported an increase in ECHOvirus 6 (E-6) infections with neurological symptoms in the Netherlands between June and August 2016. Of the 31 cases detected from January through August 2016, 15 presented with neurological symptoms. Ten of 15 neurological cases were detected in the same province and the identified viruses were genetically related. This report is to alert medical and public health professionals of the circulation of E-6 associated with neurological symptoms

Sex Differences in Outcome of Trauma Patients Presented with Severe Traumatic Brain Injury:A Multicenter Cohort Study

The objective of this study was to determine whether there is an association between sex and outcome in trauma patients presented with severe traumatic brain injury (TBI). A retrospective multicenter study was performed in trauma patients aged ≥ 16 years who presented with severe TBI (Head Abbreviated Injury Scale (AIS) ≥ 4) over a 4-year-period. Subgroup analyses were performed for ages 16–44 and ≥45 years. Also, patients with isolated severe TBI (other AIS ≤ 2) were assessed, likewise, with subgroup analysis for age. Sex differences in mortality, Glasgow Outcome Score (GOS), ICU admission/length of stay (LOS), hospital LOS, and mechanical ventilation (MV) were examined. A total of 1566 severe TBI patients were included (831 patients with isolated TBI). Crude analysis shows an association between female sex and lower ICU admission rates, shorter ICU/hospital LOS, and less frequent and shorter MV in severe TBI patients ≥ 45 years. After adjusting, female sex appears to be associated with shorter ICU/hospital LOS. Sex differences in mortality and GOS were not found. In conclusion, this study found sex differences in patient outcomes following severe TBI, potentially favoring (older) females, which appear to indicate shorter ICU/hospital LOS (adjusted analysis). Large prospective studies are warranted to help unravel sex differences in outcomes after severe TBI.</p

Superior Immunogenicity of Inactivated Whole Virus H5N1 Influenza Vaccine is Primarily Controlled by Toll-like Receptor Signalling

In the case of an influenza pandemic, the current global influenza vaccine production capacity will be unable to meet the demand for billions of vaccine doses. The ongoing threat of an H5N1 pandemic therefore urges the development of highly immunogenic, dose-sparing vaccine formulations. In unprimed individuals, inactivated whole virus (WIV) vaccines are more immunogenic and induce protective antibody responses at a lower antigen dose than other formulations like split virus (SV) or subunit (SU) vaccines. The reason for this discrepancy in immunogenicity is a long-standing enigma. Here, we show that stimulation of Toll-like receptors (TLRs) of the innate immune system, in particular stimulation of TLR7, by H5N1 WIV vaccine is the prime determinant of the greater magnitude and Th1 polarization of the WIV-induced immune response, as compared to SV- or SU-induced responses. This TLR dependency largely explains the relative loss of immunogenicity in SV and SU vaccines. The natural pathogen-associated molecular pattern (PAMP) recognized by TLR7 is viral genomic ssRNA. Processing of whole virus particles into SV or SU vaccines destroys the integrity of the viral particle and leaves the viral RNA prone to degradation or involves its active removal. Our results show for a classic vaccine that the acquired immune response evoked by vaccination can be enhanced and steered by the innate immune system, which is triggered by interaction of an intrinsic vaccine component with a pattern recognition receptor (PRR). The insights presented here may be used to further improve the immune-stimulatory and dose-sparing properties of classic influenza vaccine formulations such as WIV, and will facilitate the development of new, even more powerful vaccines to face the next influenza pandemic

The Epitope and Neutralization Mechanism of AVFluIgG01, a Broad-Reactive Human Monoclonal Antibody against H5N1 Influenza Virus

The continued spread of highly pathogenic avian influenza (HPAI) H5N1 virus underscores the importance of effective antiviral approaches. AVFluIgG01 is a potent and broad-reactive H5N1-neutralizing human monoclonal antibody (mAb) showing great potential for use either for therapeutic purposes or as a basis of vaccine development, but its antigenic epitope and neutralization mechanism have not been finely characterized. In this study, we first demonstrated that AVFluIgG01 targets a novel conformation-dependent epitope in the globular head region of H5N1 hemagglutinin (HA). By selecting mimotopes from a random peptide library in combination with computational algorithms and site-directed mutagenesis, the epitope was mapped to three conserved discontinuous sites (I-III) that are located closely at the three-dimensional structure of HA. Further, we found that this HA1-specific human mAb can efficiently block both virus-receptor binding and post-attachment steps, while its Fab fragment exerts the post-attachment inhibition only. Consistently, AVFluIgG01 could inhibit HA-mediated cell-cell membrane fusion at a dose-dependent manner and block the acquisition of pH-induced protease sensitivity. These results suggest a neutralization mechanism of AVFluIgG01 by simultaneously blocking viral attachment to the receptors on host cells and interfering with HA conformational rearrangements associated with membrane fusion. The presented data provide critical information for developing novel antiviral therapeutics and vaccines against HPAI H5N1 virus

Association of TLR7 Variants with AIDS-Like Disease and AIDS Vaccine Efficacy in Rhesus Macaques

In HIV infection, TLR7-triggered IFN-α production exerts a direct antiviral effect through the inhibition of viral replication, but may also be involved in immune pathogenesis leading to AIDS. TLR7 could also be an important mediator of vaccine efficacy. In this study, we analyzed polymorphisms in the X-linked TLR7 gene in the rhesus macaque model of AIDS. Upon resequencing of the TLR7 gene in 36 rhesus macaques of Indian origin, 12 polymorphic sites were detected. Next, we identified three tightly linked single nucleotide polymorphisms (SNP) as being associated with survival time. Genotyping of 119 untreated, simian immunodeficiency virus (SIV)-infected male rhesus macaques, including an ‘MHC adjusted’ subset, revealed that the three TLR7 SNPs are also significantly associated with set-point viral load. Surprisingly, this effect was not observed in 72 immunized SIV-infected male monkeys. We hypothesize (i) that SNP c.13G>A in the leader peptide is causative for the observed genotype-phenotype association and that (ii) the underlying mechanism is related to RNA secondary structure formation. Therefore, we investigated a fourth SNP (c.-17C>T), located 17 bp upstream of the ATG translation initiation codon, that is also potentially capable of influencing RNA structure. In c.13A carriers, neither set-point viral load nor survival time were related to the c.-17C>T genotype. In c.13G carriers, by contrast, the c.-17C allele was significantly associated with prolonged survival. Again, no such association was detected among immunized SIV-infected macaques. Our results highlight the dual role of TLR7 in immunodeficiency virus infection and vaccination and imply that it may be important to control human AIDS vaccine trials, not only for MHC genotype, but also for TLR7 genotype

Intranasal Delivery of Influenza Subunit Vaccine Formulated with GEM Particles as an Adjuvant

Nasal administration of influenza vaccine has the potential to facilitate influenza control and prevention. However, when administered intranasally (i.n.), commercially available inactivated vaccines only generate systemic and mucosal immune responses if strong adjuvants are used, which are often associated with safety problems. We describe the successful use of a safe adjuvant Gram-positive enhancer matrix (GEM) particles derived from the food-grade bacterium Lactococcus lactis for i.n. vaccination with subunit influenza vaccine in mice. It is shown that simple admixing of the vaccine with the GEM particles results in a strongly enhanced immune response. Already after one booster, the i.n. delivered GEM subunit vaccine resulted in hemagglutination inhibition titers in serum at a level equal to the conventional intramuscular (i.m.) route. Moreover, i.n. immunization with GEM subunit vaccine elicited superior mucosal and Th1 skewed immune responses compared to those induced by i.m. and i.n. administered subunit vaccine alone. In conclusion, GEM particles act as a potent adjuvant for i.n. influenza immunization

Differential Effect of TLR2 and TLR4 on the Immune Response after Immunization with a Vaccine against Neisseria meningitidis or Bordetella pertussis

Neisseria meningitidis and Bordetella pertussis are Gram-negative bacterial pathogens that can cause serious diseases in humans. N. meningitidis outer membrane vesicle (OMV) vaccines and whole cell pertussis vaccines have been successfully used in humans to control infections with these pathogens. The mechanisms behind their effectiveness are poorly defined. Here we investigated the role of Toll-like receptor (TLR) 2 and TLR4 in the induction of immune responses in mice after immunization with these vaccines. Innate and adaptive immune responses were compared between wild type mice and mice deficient in TLR2, TLR4, or TRIF. TRIF-deficient and TLR4-deficient mice showed impaired immunity after immunization. In contrast, immune responses were not lower in TLR2−/− mice but tended even to be higher after immunization. Together our data demonstrate that TLR4 activation contributes to the immunogenicity of the N. meningitidis OMV vaccine and the whole cell pertussis vaccine, but that TLR2 activation is not required