Secondary mandibular reconstruction for paediatric patients with long-term mandibular continuity defects: a retrospective study of six cases

Publication date: Available online 12 December 2016
Source:International Journal of Oral and Maxillofacial Surgery
Author(s): L. Hu, X. Yang, J. Han, Y. Wang, X. Wang, M. Zhu, J. Liu, M. Yu, C. Zhang, L. Xu
Paediatric patients with long-term mandibular continuity defects following segmental resection usually present severe functional and cosmetic deformities. Secondary mandibular reconstruction for these patients is very challenging. Literature reports on how to handle these patients are scarce. The aim of this study was to describe the authors' experience in handling those paediatric patients who have not undergone primary reconstruction, for whom the final goal of treatment is to restore a symmetrical facial appearance, masticatory function, and speech. This was a retrospective analysis of the data of six patients who underwent radical mandible resection in childhood, without immediate bone restoration, and who then underwent a secondary mandibular reconstruction procedure after reaching adulthood, during the period 2009 to 2015. The multidisciplinary treatment procedure, selection of the donor site, and reconstructive approach are discussed. Key points in relation to secondary mandibular reconstruction with the aim of achieving not only good functional and cosmetic results, but also an improvement in the paediatric patient's psychological and social outcomes, are emphasized.



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Development of Improved HDAC6 Inhibitors as Pharmacological Therapy for Axonal Charcot–Marie–Tooth Disease

Abstract

Charcot–Marie–Tooth disease (CMT) is the most common inherited peripheral neuropathy, with an estimated prevalence of 1 in 2500. The degeneration of motor and sensory nerve axons leads to motor and sensory symptoms that progress over time and have an important impact on the daily life of these patients. Currently, there is no curative treatment available. Recently, we identified histone deacetylase 6 (HDAC6), which deacetylates α-tubulin, as a potential therapeutic target in axonal CMT (CMT2). Pharmacological inhibition of the deacetylating function of HDAC6 reversed the motor and sensory deficits in a mouse model for mutant "small heat shock protein B1" (HSPB1)-induced CMT2 at the behavioral and electrophysiological level. In order to translate this potential therapeutic strategy into a clinical application, small drug-like molecules that are potent and selective HDAC6 inhibitors are essential. To screen for these, we developed a method that consisted of 3 distinct phases and that was based on the pathological findings in the mutant HSPB1-induced CMT2 mouse model. Three different inhibitors (ACY-738, ACY-775, and ACY-1215) were tested and demonstrated to be both potent and selective HDAC6 inhibitors. Moreover, these inhibitors increased the innervation of the neuromuscular junctions in the gastrocnemius muscle and improved the motor and sensory nerve conduction, confirming that HDAC6 inhibition is a potential therapeutic strategy in CMT2. Furthermore, ACY-1215 is an interesting lead molecule as it is currently tested in clinical trials for cancer. Taken together, these results may speed up the translation of pharmacological inhibition of HDAC6 into a therapy against CMT2.

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Qualitatively Understanding Patients’ and Health Professionals’ Experiences of the BRECONDA Breast Reconstruction Decision Aid

Abstract

Objective

Women diagnosed with breast cancer or ductal carcinoma in situ (DCIS), and those with a genetic susceptibility to developing this disease, face the challenging decision of whether or not to undergo breast reconstruction following mastectomy. As part of a large randomized controlled trial, this qualitative study examined women's experiences of using the Breast RECONstruction Decision Aid (BRECONDA), and health professionals' feedback regarding the impact of this resource on patients' knowledge and decision-making about breast reconstruction.

Method

Semi-structured interviews were conducted with women who accessed the BRECONDA intervention (N = 36), and with their healthcare providers (N = 6). All interviews were transcribed verbatim and subjected to thematic analysis by three independent coders.

Results

Participants reported an overall positive impression, with all interviewees endorsing this decision aid as a useful resource for women considering reconstructive surgery. Thematic analysis of patient interviews revealed four themes: Overall impressions and aesthetics; Personal relevance and utility; Introducing BRECONDA; and, Advantages and suggested improvements. Analysis of health professionals' interviews also revealed four themes: Need for BRECONDA, Impact of BRECONDA, Potential difficulties that may arise in using the decision aid, and Recommending BRECONDA to patients. Patients indicated that they derived benefit from this resource at all stages of their decision-making process, with the greatest perceived benefit being for those early in their breast reconstruction journey.

Conclusion

These findings support the use of BRECONDA as an adjunct to clinical consultation and other information sources.

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Empirically-Supported Psycho-Oncology Practices: Reflection based on Some Research Findings in Hong Kong

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Correlation of reduced interlayer charge transfer with antiphase boundary formation in BixSn1-xSe - NbSe2 heterostructures

Heterostructures of alloyed Bi<sub<x</sub>Sn_1-xSe layers, 0 ≤ x ≤ 1.0, interleaved with NbSe₂ monolayers were prepared using the modulated elemental reactants technique to investigate the occurrence of antiphase boundaries as a function of Bi concentration. A Rietveld refinement of the c-axis structure of the x = 0.50 compound revealed a reduced gap distance between the Bi plane in the Bi_xSn_1-xSe layers and the Se plane in the NbSe₂ layers relative to the end member compounds, suggesting increased interaction between the layers at this composition. High angle annular dark field scanning transmission electron microscopy images showed no antiphase boundary formation in the Bi_xSn_1-xSe layers for x = 0.24, some antiphase boundary formation when x = 0.50, and increased antiphase boundary formation for x = 0.73. Correlated with the absence of antiphase boundary formation for values of x < 0.50 and the increasing presence of antiphase boundaries for x ≥ 0.5, electrical transport measurements showed interlayer charge transfer initially increased with x, then decreased as x was increased to 0.50 and beyond.

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Differences in Behavior and Brain Activity during Hypothetical and Real Choices

Publication date: Available online 12 December 2016
Source:Trends in Cognitive Sciences
Author(s): Colin Camerer, Dean Mobbs
Real behaviors are binding consequential commitments to a course of action, such as harming another person, buying an Apple watch, or fleeing from danger. Cognitive scientists are generally interested in the psychological and neural processes that cause such real behavior. However, for practical reasons, many scientific studies measure behavior using only hypothetical or imagined stimuli. Generalizing from such studies to real behavior implicitly assumes that the processes underlying the two types of behavior are similar. We review evidence of similarity and differences in hypothetical and real mental processes. In many cases, hypothetical choice tasks give an incomplete picture of brain circuitry that is active during real choice.



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SALVAGE THERAPY WITH CEFTOLOZANE/TAZOBACTAM FOR MULTIDRUG-RESISTANT PSEUDOMONAS AERUGINOSA INFECTIONS [PublishAheadOfPrint]

Infections caused by multidrug-resistant Pseudomonas aeruginosa (MDRPA) present a major problem for therapeutic management. We report our experience in 12 patients with severe MDRPA infections (of which 6 were pneumonias) who received salvage therapy with ceftolozane/tazobactam after inappropriate empirical treatment and/or suboptimal targeted treatment. Although 10 of the 12 patients (83.3%) had septic shock, only 3 patients (25%) died during follow-up. Microbiological cure was observed in 7 patients (58.3%).

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Population Pharmacokinetic Modeling of Tenofovir in the Male Genital Tract of HIV-infected Patients [PublishAheadOfPrint]

The aim was to describe the blood plasma (BP) and seminal plasma (SP) pharmacokinetics of tenofovir (TFV) in HIV-1 infected men, to assess the role of genetic polymorphism in the variability of TFV transfer into the male genital tract and to evaluate the impact of TFV SP exposure on seminal plasma HIV load (spVL). Men from EVARIST ANRS EP49 study treated with TFV as part of their antiretroviral therapy were included in the study. A total of 248 and 217 TFV BP and SP concentrations from 129 men were available for the analysis. For pharmacogenetic assessment a total of 121 single nucleotide polymorphisms (SNP) were genotyped. Data were analyzed using a non-linear mixed effects modeling approach. TFV pharmacokinetics was best described by a two-compartment model for BP and by an effect compartment with different input and output constants for SP. TFV exposures (AUC_0-24) were higher in SP than in BP (median AUC_0-24 7.01 vs 2.97 mg.l^-1.h, respectively). Median [range] SP-to-BP AUC_0-24 ratio was 2.24 [0.53 - 34.13]. After correction for multiple testing, none of the SNPs were significantly associated with TFV transfer rate constant. The impact of TFV SP AUC_0-24 or TFV SP-to-BP AUC_0-24 ratio on spVL was not significant (p = 0.808 and 0.768, respectively). This is the first population-model describing TFV pharmacokinetics in the male genital tract. TFV SP concentrations were higher than BP concentrations. Despite TFV SP exposures higher than BP exposures, spVL was detectable for 12.2 % of men.

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Pharmacokinetics of miltefosine in children and adults with cutaneous leishmaniasis [PublishAheadOfPrint]

Aims and design: An open label, pharmacokinetics clinical trial was conducted to comparatively assess the pharmacokinetics (PK) and explore the pharmacodynamics (PD) of miltefosine in children and adults with cutaneous leishmaniasis in Colombia.

Methods: Sixty patients, 30 children aged 2-12 years and 30 adults aged 18-60 years were enrolled. Participants received miltefosine (Impavido®) at a nominal dose of 2.5 mg/kg/day for 28 days. Miltefosine concentrations were measured in plasma and peripheral blood mononuclear cells by liquid chromatography tandem-mass spectrometry of samples obtained during treatment and up to six months following completion of treatment, when therapeutic outcome was determined.

Results: Fifty-two patients cured, 5 pediatric patients failed treatment, and 3 participants were lost to follow-up. L.V. panamensis predominated among the strains isolated (42/46, 91%). Non-compartmental analysis demonstrated that plasma and intracellular miltefosine concentrations were overall, lower in children compared to adults. Exposure to miltefosine, estimated by area under the curve and C_max concentrations, was significantly lower in children both in central and intracellular compartments (p<0.01). Leishmania persistence was detected in 43% of study participants at the end of treatment and 27% at 90 days after initiation of treatment. Clinical response was not dependent on parasite elimination. In vitro miltefosine susceptibility was similar for Leishmania strains from adults and children.

Conclusion: Our results document PK differences for miltefosine in children and adults with cutaneous leishmaniasis that affect drug exposure and could influence the outcome of treatment, and provide bases for optimizing therapeutic regimens for CL in pediatric populations.

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Role of pyrazinamide in the emergence of extensively drug-resistant tuberculosis: a multi-strain mathematical model [PublishAheadOfPrint]

Several infectious diseases of global importance — e.g. HIV, tuberculosis (TB) — require prolonged treatment with combination antimicrobial regimens, typically involving high-potency "core" agents coupled with additional "companion" drugs that protect against de novo emergence of mutations conferring resistance to the core agents. Often, the most effective (or least toxic) companion agents are re-used in sequential (first-line, second-line, etc...) regimens. We used a multi-strain model of M. tuberculosis transmission in Southeast Asia to investigate how this practice might facilitate the emergence of extensive drug resistance, i.e., resistance to multiple core agents. We calibrated this model to regional TB and drug resistance data using an Approximate Bayesian Computational approach. We reported the proportion of data-consistent simulations in which the prevalence of pre-extensively drug resistant (pre-XDR) TB — defined as resistance to both first-line and second-line core agents (rifampin and fluoroquinolones) — exceeded pre-defined acceptability thresholds (1-2 cases per 100,000 population by 2035). Using pyrazinamide (the most effective companion agent) in both first-line and second-line regimens increased the proportion of simulations exceeding the pre-XDR acceptability threshold seven-fold, compared to a scenario in which patients with pyrazinamide-resistant TB received an alternative drug. Model parameters related to emergence and transmission of pyrazinamide-resistant TB and resistance amplification were among those most strongly correlated with projected pre-XDR prevalence, indicating that pyrazinamide resistance acquired during first-line treatment subsequently promotes amplification to pre-XDR TB under pyrazinamide-containing second-line treatment. These findings suggest that appropriate use of companion drugs may be critical to preventing the emergence of strains resistant to multiple core agents.

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ESBL-producing Enterobacteriaceae in France: inventory assessed by a multicentric study [PublishAheadOfPrint]

OBJECTIVES: The objective of this study was to perform an inventory of the ESBL-producing Enterobacteriaceae isolates responsible for infections in French hospitals, and to assess the mechanisms associated with ESBL diffusion.

METHODS: 200 non-redundant ESBL-producing Enterobacteriaceae strains isolated from clinical samples were collected during a multi-centric study performed in 18 representative French hospitals. Antibiotic resistance genes were identified by PCR and sequencing experiments. The clonal relatedness between isolates was investigated by the Diversilab system. ESBL-encoding plasmids were compared by PCR-based-replicon-typing and plasmid-multi-locus-sequence-typing.

RESULTS: CTX-M-15, CTX-M-1, CTX-M-14 and SHV-12 were the most prevalent ESBLs (8 to 46.5%). The three CTX-M-type EBSLs were significantly observed in Escherichia coli (37.1%, 24.2% and 21.8% respectively), and CTX-M-15 was the predominant ESBL in Klebsiella pneumoniae (81.1%). SHV-12 was associated with ESBL-encoding Enterobacter cloacae strains (37.9%). qnrB, aac(6')-Ib-cr and aac (3)-II genes were the main plasmid-mediated resistance genes, with prevalence varying between 19.5 and 45% according to the ESBLs. Molecular typing did not identify wide clonal diffusion. Plasmid analysis suggested the diffusion of few numbers of ESBL-encoding plasmids, especially in K. pneumoniae and E. cloacae. However, the ESBL-encoding genes were observed in different plasmid replicons according to the bacterial species.

CONCLUSIONS: The prevalence of ESBL subtypes is different according to the Enterobacteriaceae species. Plasmid spread is a key determinant of this epidemiology and the link observed between the ESBL-encoding plasmids and the bacterial host explain the differences observed in the Enterobacteriaceae species.

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Cephem potentiation by inactivation of non-essential genes involved in cell wall biogenesis of {beta}-lactamase-producing Escherichia coli [PublishAheadOfPrint]

Reversal of antimicrobial resistance is an appealing and largely unexplored strategy in drug discovery. The objective of this study was to identify potential targets for "helper" drugs reversing cephem resistance in Escherichia coli producing β-lactamases. A CMY-2-encoding plasmid was transferred by conjugation to seven isogenic deletion mutants exhibiting cephem hyper-susceptibility. The effect of each mutation was evaluated by comparing the MICs in the wild type and the mutant harboring the same plasmid. Mutation of two genes encoding proteins involved in cell wall biosynthesis, dapF and mrcB, restored susceptibility to cefoxitin and reduced the MICs of cefotaxime and ceftazidime, respectively, from the resistance to intermediate category according to clinical breakpoints. The same mutants harboring a CTX-M-1-encoding plasmid fell into the intermediate or susceptible category for all three drugs. Individual deletion of dapF and mrcB in a clinical isolate of CTX-M-15-producing E. coli sequence type 131 (ST131) resulted in partial reversal of ceftazidime and cefepime resistance but did not reduce MICs below susceptibility breakpoints. Growth curve analysis indicated no fitness cost in mrcB, whereas dapF had a 3-fold longer lag phase compared to the wild type, suggesting that drugs targeting DapF may display antimicrobial activity in addition to synergize with selected cephems. DapF appeared as a potential FOX helper drug target candidate since dapF inactivation resulted in synergistic potentiation of FOX in the genetic backgrounds tested. The study showed that individual inactivation of two non-essential genes involved in cell wall biogenesis potentiates cephem activity according to drug- and strain-specific patterns.

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Impact of Vancomycin Minimum Inhibitory Concentration on Treatment Outcomes in Invasive Staphylococcus aureus Infections [PublishAheadOfPrint]

There are conflicting data on the association of vancomycin minimum inhibitory concentration (VAN-MIC) with treatment outcomes in Staphylococcus aureus infections. We investigated the relationship between high VAN-MIC and 30-day mortality, and identified the risk factors for mortality in a large cohort of patients with invasive S. aureus (ISA) infections, defined by the isolation of S. aureus from a normally sterile site. Over a 2-year period, 1,027 adult patients with ISA infections were enrolled in 10 hospitals, including 673 (66%) methicillin-resistant S. aureus (MRSA) infections. There were 200 (19.5%) isolates with high VAN-MIC (≥1.5mg/L) by Etest and 87 (8.5%) by broth microdilution (BMD). The all-cause 30-day mortality rate was 27.4%. High VAN-MIC by either method was not associated with all-cause 30-day mortality, and this finding was consistent across MIC methodologies and methicillin-susceptibilities. We conclude that high VAN-MIC is not associated with increased risk of all-cause 30-day mortality in ISA infections. Our data support the view that VAN-MIC alone is not sufficient evidence to change current clinical practice.

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Protracted regional dissemination of GIM-1-producing Serratia marcescens in Western Germany [PublishAheadOfPrint]

The metallo-beta-lactamase GIM-1 has been found in various bacterial host species nearly exclusivley in Western Germany. However, not much is known about the epidemiology of GIM-1-positive Serratia marcescens. Here we report on a surprisingly protracted regional dissemination. In-hospital transmission was investigated by using conventional epidemiological tools to identify spatiotemporal links. Strain typing was performed using PFGE and whole genome sequencing (WGS). Bayesian phylogeny was used to infer the time axis of the observed occurence. Thirteen S. marcescens strains from 10 patients of 6 different German hospitals were investigated. Suspected in-hospital transmissions were confirmed by molecular typing at a higher resolution using WGS compared to PFGE. A detailed sequence analysis demonstrated a spread of one predominant strain variant, but also provided evidence for gene transfer of the bla_GIM-1 gene cassette between different strains. A Bayesian phylogenetic analysis showed that the most recent common ancestor of the identified clonal cluster can be dated back to April 1993 (95% highest posterior density interval: January 1973 - March 2003), and that this strain might have harboured the bla_GIM-1 already at that time, and therewith years before the first detection of this resistance gene in clinical specimens. This study shows a longstanding clonal and plasmid-mediated expansion of GIM-1-producing S. marcescens that might have gone unnoticed in the absence of a standardized and effective molecular screening for carbapenmases. Systematic and early detection of resistance is thus highly advisable, especially for the prevention of potentially long-term dissemination that may progress beyond control.

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In vitro antifungal susceptibility profile of 12 antifungal drugs against 55 Trichophyton schoenleinii isolated from tinea capitis favosa in Iran, Turkey and China [PublishAheadOfPrint]

Trichophyton schoenleinii is an anthropophilic dermatophyte mainly causing tinea favosa of the scalp in certain regions of the world, especially Africa and Asia. We investigated the in vitro susceptibilities of 55 T. schoenleinii collected over the last thirty years from Iran, Turkey and China against 12 antifungals using the CLSI broth-microdilution method. Our results revealed that terbinafine and ketoconazole were the most potent antifungal agents among those tested, independent of the geographical regions isolated.

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Synergistic Interactions between Hepatitis B Virus Ribonuclease H Antagonists and Other Inhibitors [PublishAheadOfPrint]

Combination therapies are standard for management of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections, however no such therapies are established for human hepatitis B virus (HBV). Recently we identified several promising inhibitors of HBV ribonuclease H (RNaseH) activity that have significant activity against viral replication in vitro. Here, we investigated in vitro antiviral efficacy of combinations of two RNaseH inhibitors with the current anti-HBV drug nucleoside analog lamivudine, with HAP12, an experimental core protein allosteric modulator, and with each other. Anti-HBV activities of the compounds were tested in a HepG2-derived cell line by monitoring intracellular core particle DNA levels, and cytotoxicity was assessed by MTS assay. The antiviral efficiencies of the drug combinations were evaluated using the median-effect equation derived from the mass-action law principle and combination index theorem of Chou and Talalay. We found that combinations of two RNaseH inhibitors from different chemical classes were synergistic with lamivudine against HBV DNA synthesis. Significant synergism was also observed for combination of the two RNaseH inhibitors. Combinations of RNaseH inhibitors with HAP12 had additive antiviral effects. Enhanced cytotoxicity was not observed in the combination experiments. Because of these synergistic and additive effects, the antiviral activity of combination of RNaseH inhibitors with drugs that act by two different mechanisms and with each other can be achieved by administering the compounds in combination at doses below the respective single drug doses.

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Safety, tolerability, and pharmacokinetics of the respiratory syncytial virus-prefusion F-targeting monoclonal antibody with an extended half-life, MEDI8897, in healthy adults [PublishAheadOfPrint]

Prevention of respiratory syncytial virus (RSV) illness in infants is a major public health priority, but there is no approved vaccine. Palivizumab is a monoclonal antibody that provides RSV prophylaxis but requires 5 monthly injections and is approved only for infants who experience the greatest morbidity and mortality from RSV. Thus, there remains a significant unmet medical need for prevention of RSV disease in healthy infants. MEDI8897 is a recombinant human RSV monoclonal antibody with a modified Fc region that extends its half-life and is being developed as RSV prophylaxis for all infants. In this phase 1, first-in-human, placebo-controlled study, 136 healthy adults were randomized to receive a single dose of MEDI8897 (n = 102) or placebo (n = 34) in 1 of 5 cohorts (300, 1000, or 3000 mg intravenous or 100 or 300 mg intramuscular [IM]) and were followed for 360 days. The mean half-life of MEDI8897 was 85 to 117 days across dose groups, and bioavailability after 300-mg IM dose administration was 77%. Time to maximum concentration following IM dosing was 5 to 9 days. Antidrug antibody (ADA) responses were detected in a similar proportion of placebo (15.2%) and MEDI8897 (13.7%) recipients. The safety profile of MEDI8897 was similar to placebo. These results support clinical studies of the IM administration of a single dose of MEDI8897 in the target population of infants to provide protection for the duration of the RSV season.

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Synthesis and evaluation of chirally defined side chain variants of 7-chloro-4-aminoquinoline to overcome drug resistance in malaria chemotherapy. [PublishAheadOfPrint]

A novel 4-aminoquinoline derivative ((S)-7-chloro-N-(4-methyl-1-(4-methylpiperazin-1-yl)pentan-2-yl)-quinolin-4-amine triphosphate) exhibiting curative activity against chloroquine resistant malaria parasite has been identified for preclinical development as a blood schizonticidal agent. The lead molecule selected after detailed SAR studies, has good solid state properties, and has promising activity against in vitro and in vivo experimental malaria models. The in vitro ADME parameters have indicated favourable drug like profile.

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Fungal CYP51 Inhibitors VT-1161 and VT-1129 exhibit strong in vitro activity against Candida glabrata and C. krusei isolates clinically resistant to azole and echinocandin antifungal compounds [PublishAheadOfPrint]

In vitro activity of fungal CYP51 inhibitors VT-1161 and VT-1129 was determined for Candida glabrata (N=34) and C. krusei (N=50). C. glabrata isolates were screened for FKS mutations. All isolates were resistant clinically and/or in vitro to one or more standard antifungal compounds. VT-1161 and VT-1129 MICs for all isolates were at least 5-fold below achievable human plasma levels for VT-1161. VT-1161 and VT-1129 are promising for treatment of resistant C. glabrata and C. krusei infections.

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Effects of Oritavancin on Coagulation Tests in the Clinical Laboratory [PublishAheadOfPrint]

Previous studies have shown that some lipoglycopeptide and lipopeptide antimicrobial agents may cause falsely elevated values for some phospholipid-dependent coagulation tests. The effect of oritavancin, a lipoglycopeptide antibiotic, on coagulation test results was explored using pooled human plasma samples spiked with drug and in a clinical study after an infusion of a single 1200 mg intravenous dose of oritavancin in normal healthy volunteers. Pooled plasma with oritavancin added ex vivo showed concentration-dependent prolongation of prothrombin time/international normalized ratio (PT/INR), activated partial thromboplastin time (aPTT) and the dilute Russell viper venom test (DRVVT). In contrast, oritavancin had no effect on the activated protein C resistance assay, chromogenic anti-factor Xa assay (anti-FXa), thrombin time, and an immunoassay for the laboratory diagnosis of heparin-induced thrombocytopenia. In participants that received a single dose of oritavancin, elevations of PT/INR, aPTT, DRVVT, activated clotting time, and silica clot time occurred with the maximum time-to-resolution of test interference determined to be 12, 120, 72, 24, and 18 h, respectively. The anti-FXa assay was unaffected whereas transient elevations in D-dimer were observed in 30% of participants, with a maximum time-to-resolution of 72 h. Although oritavancin has no impact on the coagulation system in vivo, a single dose of oritavancin can produce falsely elevated values of some coagulation tests used to monitor hemostasis. The interference of oritavancin on affected tests is transient and the tests revert to normal ranges within specified times after dosing.

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Chromosome-encoded broad-spectrum Ambler class A {beta}-lactamase RUB-1 from Serratia rubidaea [PublishAheadOfPrint]

Whole genome sequencing of Serratia rubidaea CIP 103234^T revealed a chromosomally-located Ambler class A β-lactamase gene. The gene was cloned, and the β-lactamase, RUB-1, was characterized. RUB-1 displayed 74% and 73 % amino acid sequence identity with GIL-1 and TEM-1 penicillinases, respectively, and its substrate profile was similar to that of these latter β-lactamases. 5' RACE analysis revealed promoter sequences highly divergent from E. coli ⁷⁰ consensus sequence. This work further illustrates the heterogeneity of ß-lactamases among Serratia spp.

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β-Amyloid triggers aberrant over-scaling of homeostatic synaptic plasticity

The over-production of β-amyloid (Aβ) has been strongly correlated to neuronal dysfunction and altered synaptic plasticity in Alzheimer's disease (AD). Accordingly, it has been proposed that disrupted synaptic transmission and neuronal network instability underlie memory failure that is evident in the early phases of AD. Homeostatic synaptic plasticity (HSP) serves to restrain neuronal activity within a physiological range. Therefore a disruption of this mechanism may lead to destabilization in synaptic and neural circuit function. Here, we report that during HSP by neuronal activity deprivation, application of Aβ results in an aberrant over-response of the up-regulation of AMPA receptor (AMPAR)-mediated synaptic currents and cell-surface AMPAR expression. In the visual cortex, in vivo HSP induced by visual deprivation shows a similar over-response following an Aβ local injection. Aβ increases the expression of GluA2-lacking, calcium permeable AMPARs (CP-AMPARs), which are required for the initiation, but not maintenance of HSP. Both GluA2-lacking and GluA2-containing AMPARs contribute to the Aβ-mediated over-scaling of HSP. We also find that Aβ induces the dissociation of HDAC1 from the miR124 transcription factor EVI1, leading to an up-regulation of miR124 expression and increased amount of CP-AMPARs. Thus, via aberrant stimulation of miR124 expression and biogenesis of CP-AMPARs, Aβ is able to induce an over response in HSP. This Aβ-mediated dysregulation in homeostatic plasticity may play an important role in the pathogenesis of altered neural function and memory deficits in the early stages of AD.

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The curious case of an internal pilot in a multicentre randomised trial—time for a rethink?

Multicentre randomised trials are complex projects with many operational uncertainties. The embedding of a formal check upon study progress and viability at a pre-specified time point (sometimes referred to as an 'internal pilot') is becoming increasingly common within multicentre pragmatic randomised trials. However, it is worth considering this practice. We argue that most, if not all, multicentre trials have reassessment of the recruitment strategy and study processes whilst the study is running. Additionally, we propose discontinuation of the 'internal/external pilot study' terminology. Instead, we suggest for an alternative taxonomy along with greater recognition of the process of refinement which routinely occurs in trials and transparent reporting of it.

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Safety and efficacy of vinorelbine in combination with pertuzumab and trastuzumab for first-line treatment of patients with HER2-positive locally advanced or metastatic breast cancer: VELVET Cohort 1 final results

Background: Pertuzumab, trastuzumab, and docetaxel is standard of care for first-line treatment of HER2-positive metastatic breast cancer (MBC). However, alternative chemotherapy partners are required to align with patient/physician preferences and to increase treatment flexibility. We report VELVET Cohort 1 results in which the efficacy and safety of pertuzumab and trastuzumab, administered sequentially in separate infusions, followed by vinorelbine, were evaluated. Cohort 2, where pertuzumab and trastuzumab were administered in a single infusion, followed by vinorelbine, recruited after Cohort 1 was fully enrolled, will be reported later. Methods: In this multicenter, two-cohort, open-label, phase II study, patients with HER2-positive locally advanced or MBC who had not received chemotherapy or biological therapy for their advanced disease received 3-weekly pertuzumab (840 mg loading, 420 mg maintenance doses) and trastuzumab (8 mg/kg loading, 6 mg/kg maintenance doses), followed by vinorelbine (25 mg/m 2 initial dose, 30–35 mg/m 2 maintenance doses) on days 1 and 8 or 2 and 9 of each 3-weekly cycle. Study treatment was given until investigator-assessed disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate (ORR) in patients with measurable disease at baseline per RECIST v1.1. Secondary endpoints included progression-free survival (PFS) and safety. Results: Cohort 1 enrolled 106 patients. Investigator-assessed ORR was 74.2% (95% CI 63.8–82.9) in intent-to-treat patients with measurable disease (89/106 [84.0%]). Median PFS was 14.3 months (95% CI 11.2–17.5) in the intent-to-treat population. Treatment was reasonably well tolerated, with no unexpected toxicities. Diarrhea (61/106 patients [57.5%]) and neutropenia (54/106 [50.9%]) were the most common adverse events (AEs); neutropenia (33/106 [31.1%]) and leukopenia (14/106 [13.2%]) were the most common grade ≥3 AEs. Serious AEs were reported in 32/106 (30.2%) patients. AEs led to study drug discontinuation in 36/106 patients (34.0%). Eighteen of 106 patients (17.0%) had AEs suggestive of congestive heart failure; however, there were no confirmed cases. Conclusions: The vinorelbine, pertuzumab, and trastuzumab combination is active and reasonably well tolerated. This regimen offers an alternative for patients who cannot receive docetaxel for first-line treatment of HER2-positive locally advanced or MBC.Trial registrationClinicalTrials.gov: NCT01565083, registered on 26 March 2012.

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Metabolic profiling of pregnancy: cross-sectional and longitudinal evidence

Background: Pregnancy triggers well-known alterations in maternal glucose and lipid balance but its overall effects on systemic metabolism remain incompletely understood. Methods: Detailed molecular profiles (87 metabolic measures and 37 cytokines) were measured for up to 4260 women (24–49 years, 322 pregnant) from three population-based cohorts in Finland. Circulating molecular concentrations in pregnant women were compared to those in non-pregnant women. Metabolic profiles were also reassessed for 583 women 6 years later to uncover the longitudinal metabolic changes in response to change in the pregnancy status. Results: Compared to non-pregnant women, all lipoprotein subclasses and lipids were markedly increased in pregnant women. The most pronounced differences were observed for the intermediate-density, low-density and high-density lipoprotein triglyceride concentrations. Large differences were also seen for many fatty acids and amino acids. Pregnant women also had higher concentrations of low-grade inflammatory marker glycoprotein acetyls, higher concentrations of interleukin-18 and lower concentrations of interleukin-12p70. The changes in metabolic concentrations for women who were not pregnant at baseline but pregnant 6 years later (or vice versa) matched (or were mirror-images of) the cross-sectional association pattern. Cross-sectional results were consistent across the three cohorts and similar longitudinal changes were seen for 653 women in 4-year and 497 women in 10-year follow-up. For multiple metabolic measures, the changes increased in magnitude across the three trimesters. Conclusions: Pregnancy initiates substantial metabolic and inflammatory changes in the mothers. Comprehensive characterisation of normal pregnancy is important for gaining understanding of the key nutrients for fetal growth and development. These findings also provide a valuable molecular reference in relation to studies of adverse pregnancy outcomes.

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New classification of endometrial cancers: the development and potential applications of genomic-based classification in research and clinical care

Endometrial carcinoma (EC) is the fourth most common cancer in women in the developed world. Classification of ECs by histomorphologic criteria has limited reproducibility and better tools are needed to distinguish these tumors and enable a subtype-specific approach to research and clinical care. Based on the Cancer Genome Atlas, two research teams have developed pragmatic molecular classifiers that identify four prognostically distinct molecular subgroups. These methods can be applied to diagnostic specimens (e.g., endometrial biopsy) with the potential to completely change the current risk stratification systems and enable earlier informed decision making. The evolution of genomic classification in ECs is shared herein, as well as potential applications and discussion of the essential research still needed in order to optimally integrate molecular classification in to current standard of care.

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Microbial phenomics information extractor (MicroPIE): a natural language processing tool for the automated acquisition of prokaryotic phenotypic characters from text sources

Background: The large-scale analysis of phenomic data (i.e., full phenotypic traits of an organism, such as shape, metabolic substrates, and growth conditions) in microbial bioinformatics has been hampered by the lack of tools to rapidly and accurately extract phenotypic data from existing legacy text in the field of microbiology. To quickly obtain knowledge on the distribution and evolution of microbial traits, an information extraction system needed to be developed to extract phenotypic characters from large numbers of taxonomic descriptions so they can be used as input to existing phylogenetic analysis software packages. Results: We report the development and evaluation of Microbial Phenomics Information Extractor (MicroPIE, version 0.1.0). MicroPIE is a natural language processing application that uses a robust supervised classification algorithm (Support Vector Machine) to identify characters from sentences in prokaryotic taxonomic descriptions, followed by a combination of algorithms applying linguistic rules with groups of known terms to extract characters as well as character states. The input to MicroPIE is a set of taxonomic descriptions (clean text). The output is a taxon-by-character matrix—with taxa in the rows and a set of 42 pre-defined characters (e.g., optimum growth temperature) in the columns. The performance of MicroPIE was evaluated against a gold standard matrix and another student-made matrix. Results show that, compared to the gold standard, MicroPIE extracted 21 characters (50%) with a Relaxed F1 score > 0.80 and 16 characters (38%) with Relaxed F1 scores ranging between 0.50 and 0.80. Inclusion of a character prediction component (SVM) improved the overall performance of MicroPIE, notably the precision. Evaluated against the same gold standard, MicroPIE performed significantly better than the undergraduate students. Conclusion: MicroPIE is a promising new tool for the rapid and efficient extraction of phenotypic character information from prokaryotic taxonomic descriptions. However, further development, including incorporation of ontologies, will be necessary to improve the performance of the extraction for some character types.

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Developing an approach to assessing the political feasibility of global collective action and an international agreement on antimicrobial resistance

Background: Antimicrobial resistance (AMR) is a global issue. International trade, travel, agricultural practices, and environmental contamination all make it possible for resistant microbes to cross national borders. Global collective action is needed in the form of an international agreement or other mechanism that brings states together at the negotiation table and commits them to adopt or implement policies to limit the spread of resistant microorganisms. This article describes an approach to assessing whether political and stakeholder interests can align to commit to tackling AMR. Methods: Two dimensions affecting political feasibility were selected and compared across 82 countries: 1) states' global influence and 2) self-interest in addressing AMR. World Bank GDP ranking was used as a proxy for global influence, while human antibiotic consumption (10-year percent change) was used as a proxy for self-interest in addressing AMR. We used these data to outline a typology of four country archetypes, and discuss how these archetypes can be used to understand whether a proposed agreement may have sufficient support to be politically feasible. Results: Four types of countries exist within our proposed typology: 1) wealthy countries who have the expertise and financial resources to push for global collective action on AMR, 2) wealthy countries who need to act on AMR, 3) countries who require external assistance to act on AMR, and 4) neutral countries who may support action where applicable. Any international agreement will require substantial support from countries of the first type to lead global action, and from countries of the second type who have large increasing antimicrobial consumption levels. A large number of barriers exist that could derail efforts towards global collective action on AMR; issues of capacity, infrastructure, regulation, and stakeholder interests will need to be addressed in coordination with other actors to achieve an agreement on AMR. Conclusions: Achieving a global agreement on access, conservation, and innovation – the three pillars of AMR – will not be easy. However, smaller core groups of interested Initiator and Pivotal Countries could develop policy and resolve many issues. If highly influential countries take the lead, agreements could then be scaled up to achieve global action.

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Desire for predictive testing for Alzheimer’s disease and impact on advance care planning: a cross-sectional study

Background: It is unknown whether older adults in the United States would be willing to take a test predictive of future Alzheimer's disease, or whether testing would change behavior. Using a nationally representative sample, we explored who would take a free and definitive test predictive of Alzheimer's disease, and examined how using such a test may impact advance care planning. Methods: A cross-sectional study within the 2012 Health and Retirement Study of adults aged 65 years or older asked questions about a test predictive of Alzheimer's disease (N = 874). Subjects were asked whether they would want to take a hypothetical free and definitive test predictive of future Alzheimer's disease. Then, imagining they knew they would develop Alzheimer's disease, subjects rated the chance of completing advance care planning activities from 0 to 100. We classified a score > 50 as being likely to complete that activity. We evaluated characteristics associated with willingness to take a test for Alzheimer's disease, and how such a test would impact completing an advance directive and discussing health plans with loved ones. Results: Overall, 75% (N = 648) of the sample would take a free and definitive test predictive of Alzheimer's disease. Older adults willing to take the test had similar race and educational levels to those who would not, but were more likely to be ≤75 years old (odds ratio 0.71 (95% CI 0.53–0.94)). Imagining they knew they would develop Alzheimer's, 81% would be likely to complete an advance directive, although only 15% had done so already. Conclusions: In this nationally representative sample, 75% of older adults would take a free and definitive test predictive of Alzheimer's disease. Many participants expressed intent to increase activities of advance care planning with this knowledge. This confirms high public interest in predictive testing for Alzheimer's disease and suggests this may be an opportunity to engage patients in advance care planning discussions.

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Exploratory analysis of CD63 and CD203c expression in basophils from hazelnut sensitized and allergic individuals

Background: Sensitization to hazelnut (HN) is frequent and requires clarification to determine whether this sensitization is clinically relevant. The aim of this study was to investigate basophil activation profiles in HN-sensitized and allergic subjects. Methods: Basophil activation was determined by flow cytometric analyses of CD63 and CD203c expression using several HN allergen concentrations. Depending on their clinical reaction pattern, an oral allergy symptom group (OAS, n = 20), a systemic reaction group (n = 12) and a sensitized group without clinical symptoms (n = 20) were identified. Additionally, 10 non-allergic and non-sensitized individuals served as controls. Results: CD63 and CD203c expression differed between allergic (OAS and systemic group) and sensitized subjects. The HN concentration required to activate 30% of CD203c + basophils [effective concentration (EC)30] was significantly higher in sensitized versus the allergic group (p = 0.0089). This was more pronounced when the basophil allergen threshold sensitivity (CD-sens) was calculated (CD63: p = 0.018; CD203c: p = 0.009). Conclusion: Our data indicate that the basophil activation test may provide information to better distinguish between sensitized and allergic subjects if several allergen concentrations are considered. CD203c expression displayed a better discrimination compared to CD63; therefore, its diagnostic value might be superior compared with CD63.

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Stabbing energy and force required for pocket-knives to pierce ribs

Abstract

Purpose

In addition to reconstructing the course of events, the medical examiner will often have to answer questions regarding the force necessary to inflict a certain injury in stabbing incidents. Several groups have examined the force needed to penetrate soft-tissue and clothing; however, no studies addressing the energy needed for penetrating ribs exist. Therefore, we decided to investigate this force on an animal model.

Method

Ribs from healthy, 8 to 10-month-old pigs were used as a substitute for human ribs. These ribs were then stabbed either transversely or longitudinally with two different pocket-knife blades, namely a Swiss Army pocket knife and a sturdier pocket knife (Classic Schnitzmesser, Herbertz Solingen) dropped from a drop-tower at defined heights and therefore defined energies.

Results

Longitudinally orientated stabs showed complete piercing of the ribs at approximately 11 Joules (J) or with a stabbing force in excess of 906 Newton (N) for both blade types. Transversely orientated stabs, however, displayed complete piercing between 11 and 16 J, or in excess of 1198 N, with the sturdy pocket knife tending to require a little more energy than the Swiss army pocket knife.

Conclusions

Young adult porcine ribs are completely pierced by pocket knife blades at energies between 11 and 16 J. Assuming the porcine ribs are comparable to those ribs of young adult humans, our results indicate that a complete penetration of the chest wall through the ribs by stabbing with a pocket knife is rather easily achieved.

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Green pus in the subdural space and within the ventricles: an uncommon finding but a straightforward macroscopic diagnosis

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Make-up and love bites: two reports about exceptional cases of self-inflicted “injuries”

Abstract

Self-inflicted injuries and their differentiation from inflicted injuries may have severe legal implications. The detection of these injuries is an important task in clinical forensic medicine. We present two cases of skin discolorations caused by using make-up and suction of the skin which have only rarely been reported. In the first case a 19-year-old woman asserted she was punched against her left clavicle and her right eye by a perpetrator, and that during the following forced sexual intercourse she had been bitten on the neck. On medicolegal examination 3 days later dark blue, shimmering discolorations at her right eyebrow, the left side of the neck and the left clavicle were seen. At first sight these discolorations appeared as bruises; however, they could easily be removed by a simple wipe with a finger. In the second reported case a 23-year-old woman reported she had been assaulted by two men who forcefully pressed her against a wall, partially undressed her and forced her to touch and rub one man's penis. Medicolegal examination 32 h after the incident revealed several round to oval shaped, reddish to brown discolorations on both of her upper arms resembling so-called love bites created by suction. In both cases the preliminary investigation by the public prosecutor were closed. However, case 1 is still subject to legal investigations due to false incrimination. Self-infliction of injuries should always be considered in forensic examinations, even if they do not follow the classical pattern.

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Customary law, traditional punishment, and death in the Anangu Pitjantjatjara Yankunytjatjara (APY) lands of Central Australia

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Unintentional asphyxia, SIDS, and medically explained deaths: a descriptive study of outcomes of child death review (CDR) investigations following sudden unexpected death in infancy

Abstract

Background

A comprehensive child death review (CDR) program was introduced in England and Wales in 2008, but as yet data have only been analyzed at a local level, limiting the learning from deaths. The aim of this study is to describe the profile of causes and risk factors for sudden unexpected death in infancy (SUDI) as determined by the new CDR program.

Methods

This was a descriptive outcome study using data from child death overview panel Form C for SUDI cases dying during 2010–2012 in the West Midlands region of England. The main outcome measures were: cause of death, risk factors and potential preventability of death, and determination of deaths probably due to unintentional asphyxia.

Results

Data were obtained for 65/70 (93 %) SUDI cases. 20/65 (31 %) deaths were initially categorized as due to medical causes; 21/65 (32 %) as SIDS; and 24/65 (37 %) as undetermined. Reanalysis suggested that 2/21 SIDS and 7/24 undetermined deaths were probably due to unintentional asphyxia, with 6 of these involving co-sleeping and excessive parental alcohol consumption. Deaths classified as "undetermined" had significantly higher total family and environmental risk factor scores (mean 2.6, 95 % CI 2.0–3.3) compared to those classified as SIDS (mean 1.6, 95 % CI 1.2–1.9), or medical causes for death (mean 1.1, 95 % CI 0.8–1.3). 9/20 (47 %) of medical deaths, 19/21 (90 %) SIDS, and 23/24 (96 %) undetermined deaths were considered to be potentially preventable. There were inadequacies in medical provision identified in 5/20 (25 %) of medically explained deaths.

Conclusions

The CDR program results in detailed information about risk factors for SUDI cases but failed to recognize deaths probably due to unintentional asphyxia. The misclassification of probable unintentional asphyxial deaths and SIDS as "undetermined deaths" is likely to limit learning from these deaths and inhibit prevention strategies. Many SUDI occurred in families with mental illness, substance misuse and chaotic lifestyles and most in unsafe sleep environments. This knowledge could be used to better target safe sleep advice for vulnerable families and prevent SUDI in the future.

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The impact of luminance on tonic and phasic pupillary responses to sustained cognitive load

Publication date: Available online 12 December 2016
Source:International Journal of Psychophysiology
Author(s): Vsevolod Peysakhovich, François Vachon, Frédéric Dehais
Pupillary reactions independent of light conditions have been linked to cognition for a long time. However, the light conditions can impact the cognitive pupillary reaction. Previous studies underlined the impact of luminance on pupillary reaction, but it is still unclear how luminance modulates the sustained and transient components of pupillary reaction – tonic pupil diameter and phasic pupil response. In the present study, we investigated the impact of the luminance on these two components under sustained cognitive load. Fourteen participants performed a novel working memory task combining mathematical computations with a classic n-back task. We studied both tonic pupil diameter and phasic pupil response under low (1-back) and high (2-back) working memory load and two luminance levels (gray and white). We found that the impact of working memory load on the tonic pupil diameter was modulated by the level of luminance, the increase in tonic pupil diameter with the load being larger under lower luminance. In contrast, the smaller phasic pupil response found under high load remained unaffected by luminance. These results showed that luminance impacts the cognitive pupillary reaction – tonic pupil diameter (phasic pupil response) being modulated under sustained (respectively, transient) cognitive load. These findings also support the relationship between the locus-coeruleus system, presumably functioning in two firing modes – tonic and phasic – and the pupil diameter. We suggest that the tonic pupil diameter tracks the tonic activity of the locus-coeruleus while phasic pupil response reflects its phasic activity. Besides, the designed novel cognitive paradigm allows the simultaneous manipulation of sustained and transient components of the cognitive load and is useful for dissociating the effects on the tonic pupil diameter and phasic pupil response.



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Impact of cystic fibrosis disease on archaea and bacteria composition of gut microbiota

Cystic fibrosis is often associated with intestinal inflammation due to several factors, including altered gut microbiota composition. In this study, we analyzed the fecal microbiota among patients with cystic fibrosis of 10–22 years of age, and compared the findings with age-matched healthy subjects. The participating patients included 14 homozygotes and 14 heterozygotes with the delF508 mutation, and 2 heterozygotes presenting non-delF508 mutations. We used PCR-DGGE and qPCR to analyze the presence of bacteria, archaea and sulfate-reducing bacteria. Overall, our findings confirmed disruption of the cystic fibrosis gut microbiota. Principal component analysis of the qPCR data revealed no differences between homozygotes and heterozygotes, while both groups were distinct from healthy subjects who showed higher biodiversity. Archaea were under the detection limit in all homozygotes subjects, whereas methanogens were detected in 62% of both cystic fibrosis heterozygotes and healthy subjects. Our qPCR results revealed a low frequency of sulfate-reducing bacteria in the homozygote (13%) and heterozygote (13%) patients with cystic fibrosis compared with healthy subjects (87.5%). This is a pioneer study showing that patients with cystic fibrosis exhibit significant reduction of H₂-consuming microorganisms, which could increase hydrogen accumulation in the colon and the expulsion of this gas through non-microbial routes.

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The hot oyster: levels of virulent Vibrio parahaemolyticus strains in individual oysters

Vibrio parahaemolyticus is the leading cause of seafood-associated gastroenteritis and is most commonly transmitted by raw oysters. Consequently, detection of virulent strains of this organism in oysters is a primary concern for seafood safety. Vibrio parahaemolyticus levels were determined in 110 individual oysters harvested from two sampling sites in SC, USA. The majority of oysters (98%) contained low levels of presumptive V. parahaemolyticus. However, two healthy oysters contained presumptive V. parahaemolyticus numbers that were unusually high. These two 'hot' oysters contained levels of presumptive V. parahaemolyticus within the gills that were ~100-fold higher than the average for other oysters collected at the same date and location. Current V. parahaemolyticus detection practices require homogenizing a dozen oysters pooled together to determine V. parahaemolyticus numbers, a procedure that would dilute out V. parahaemolyticus in these 'hot' oysters. This study demonstrates the variability of V. parahaemolyticus densities taken from healthy, neighboring individual oysters in the environment. Additionally, environmental V. parahaemolyticus isolates were screened for the virulence-related genes, tdh and trh, using improved polymerase chain reaction primers and protocols. We detected these genes, previously thought to be rare in environmental isolates, in approximately half of the oyster isolates.

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In vitro fermentation of B-GOS: impact on faecal bacterial populations and metabolic activity in autistic and non-autistic children

Children with autism spectrum disorders (ASD) often suffer gastrointestinal problems consistent with imbalances in the gut microbial population. Treatment with antibiotics or pro/prebiotics has been postulated to regulate microbiota and improve gut symptoms, but there is a lack of evidence for such approaches, especially for prebiotics. This study assessed the influence of a prebiotic galactooligosaccharide (B-GOS) on gut microbial ecology and metabolic function using faecal samples from autistic and non-autistic children in an in vitro gut model system. Bacteriology was analysed using flow cytometry combined with fluorescence in situ hybridization and metabolic activity by HPLC and ¹H-NMR. Consistent with previous studies, the microbiota of children with ASD contained a higher number of Clostridium spp. and a lower number of bifidobacteria compared with non-autistic children. B-GOS administration significantly increased bifidobacterial populations in each compartment of the models, both with autistic and non-autistic-derived samples, and lactobacilli in the final vessel of non-autistic models. In addition, changes in other bacterial population have been seen in particular for Clostridium, Rosburia, Bacteroides, Atopobium, Faecalibacterium prausnitzii, Sutterella spp. and Veillonellaceae. Furthermore, the addition of B-GOS to the models significantly altered short-chain fatty acid production in both groups, and increased ethanol and lactate in autistic children.

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Exploratory analysis of CD63 and CD203c expression in basophils from hazelnut sensitized and allergic individuals

Sensitization to hazelnut (HN) is frequent and requires clarification to determine whether this sensitization is clinically relevant. The aim of this study was to investigate basophil activation profiles in HN...

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Exploratory analysis of CD63 and CD203c expression in basophils from hazelnut sensitized and allergic individuals

Sensitization to hazelnut (HN) is frequent and requires clarification to determine whether this sensitization is clinically relevant. The aim of this study was to investigate basophil activation profiles in HN...

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European Society of Neuroradiology (ESNR)

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Annual Report 2016

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Dual-targeting nanoparticles for in vivo delivery of suicide genes to chemotherapy-resistant ovarian cancer cells

Ovarian cancer is the most lethal gynecologic cancer. Claudin-3 and-4, the receptors for Clostridium Perfringens Enterotoxin (CPE), are overexpressed in over 70% of these tumors. Here we synthesized and characterized poly(lactic-co-glycolic-acid) (PLGA) nanoparticles (NP) modified with the carboxi-terminal binding domain of CPE (c-CPE-NP) for the delivery of suicide gene therapy to chemotherapy-resistant ovarian cancer cells. As a therapeutic payload we generated a plasmid encoding for the Diphteria Toxin subunit-A (DT-A) under the transcriptional control of the p16 promoter, a gene highly differentially expressed in ovarian cancer cells. Flow cytometry and immunofluorescence demonstrated that c-CPE-NPs encapsulating the CMV GFP plasmid (CMV GFP c-CPE-NP) were significantly more efficient than control NP modified with a scrambled peptide (CMV GFP scr-NP) in transfecting primary chemotherapy-resistant ovarian tumor cell lines in vitro (p=0.03). Importantly, c-CPE-NPs encapsulating the p16 DT-A vector (p16 DT-A c-CPE-NP) were significantly more effective than control p16 DT-A scr-NP in inducing ovarian cancer cell death in vitro (% cytotoxicity: mean ± STDV = 32.9 ± 0.15 and 7.45 ± 7.93, respectively, p=0.03). In vivo bio-distribution studies demonstrated efficient transfection of tumor cells within 12 hours after intraperitoneal (IP) injection of CMV GFP c-CPE-NP in mice harboring chemotherapy-resistant ovarian cancer xenografts. Finally, multiple IP injections of p16 DT-A c-CPE-NP resulted in a significant inhibition of tumor growth compared to control NP in chemotherapy-resistant tumor-bearing mice (p=0.041). p16 DT-A c-CPE-NP may represent a novel dual-targeting therapeutic approach for the selective delivery of gene therapy to chemotherapy-resistant ovarian cancer cells.

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Dual inhibition of key proliferation signaling pathways in triple negative breast cancer cells by a novel derivative of Taiwanin A

The treatment of breast cancer cells obtained by blocking the aberrant activation of the proliferation signaling pathways PI-3K/Akt/mTOR and MEK/ERK has received considerable attention in recent years. Previous studies showed that Taiwanin A inhibited the proliferation of several types of cancer cells. In this study, we report that 3,4-bis-3,4,5- trimethoxybenzylidene-dihydrofuran (BTMB), a novel derivative of Taiwanin A, significantly inhibited the proliferation of triple negative breast cancer (TNBC) cells both in vitro and in vivo. The results show that BTMB inhibited the proliferation of human TNBC cells by the induction of cell cycle arrest and apoptosis in a dose-dependent fashion. BTMB inhibited the expression of β-catenin, cdc2 and the cell cycle regulatory proteins, cyclin A, cyclin D1 and cyclin E. The mechanism of action was associated with the suppression of cell survival signaling through inactivation of the Akt and ERK 1/2 signaling pathways. Moreover, BTMB induced cell apoptosis through an increase in the expression of BAX, cleaved-caspase-3 and cleaved-poly ADP-ribose polymerase (PARP). Moreover, BTMB inhibited TNBC cell colony formation and sensitized TNBC cells to cisplatin, a chemotherapeutic drug. In a TNBC mouse-xenograft model, BTMB significantly inhibited the growth of mammary carcinomas through decreased expression of cyclin D1. BTMB was shown to significantly suppress the growth of mammary carcinoma and therefore to have potential as an anti-cancer therapeutic agent.

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Measuring safety of inhaled corticosteroids in asthma

Despite evidence demonstrating generally excellent therapeutic ratios for inhaled corticosteroids (ICSs) in asthma treatment, many clinicians and patients have ongoing concerns regarding their safety. To frame discussions of ICS safety, it is important to understand how safety is measured.

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Immunodominance in allergic T-cell reactivity to Japanese cedar in different geographic cohorts

Japanese cedar (JC) pollen is a common trigger for allergic rhinitis in Japan. Pollen proteins targeted by IgE, including Cry j 1 and Cry j 2, and isoflavone reductase (IFR) have been identified.

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Inhalation devices, delivery systems, and patient technique

In real-life clinical settings, physicians often consider the properties of various inhaled corticosteroids (ICSs), but typically little consideration is given to the properties of different inhalers and formulations.

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Inhaled corticosteroids

Both slowed growth in children and reduced bone mineral density (BMD) are systemic effects of corticosteroids, and there is concern about the degree to which these systemic effects affect growth and BMD.

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Instructions for Authors

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Development and usability of a computer-tailored pedometer-based physical activity advice for breast cancer survivors

This observational study aimed to adapt a computer-tailored step advice for the general population into a feasible advice for breast cancer survivors and to test its usability. First, several adaptations were made to the original design (adding cancer-related physical activity (PA) barriers and beliefs, and self-management strategies to improve survivors' personal control). Second, the adapted advice was evaluated in two phases: (1) a usability testing in healthy women (n = 3) and survivors (n = 6); and (2) a process evaluation during 3 weeks in breast cancer survivors (n = 8). Preliminary usability testing revealed no problems during logging-in; however, three survivors misinterpreted some questions. After refining the questionnaire and advice, survivors evaluated the advice as interesting, attractive to read, comprehensible and credible. Inactive survivors found the advice novel, but too long. The process evaluation indicated that the majority of the women (n = 5/8) reported increased steps. Monitoring step counts by using a pedometer was perceived as an important motivator to be more active. To conclude, this study provides initial support for the usability and acceptability of a computer-tailored pedometer-based PA advice for breast cancer survivors. After testing efficacy and effectiveness of this intervention, this tool can broaden the reach of PA promotion in breast cancer survivors.

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The effect of a reduced power quality on the energy efficiency of stand-alone generator systems

It has already been thoroughly validated that the efficiency of direct online motors is susceptible towards certain power quality parameters such as voltage unbalance or harmonic voltage distortion. It can be assumed that electrical generators are also susceptible to these parameters, but to the author's knowledge this effect has not yet been evaluated in scientific studies. This paper starts from the well studied additional loss mechanisms inside induction motors and consequently efforts are presented to translate these effects to stand-alone synchronous generators. Subsequently, the paper presents extensive measurements related to the effect of unbalanced and non-linear loading on the energy efficiency of 2 different 4kVA stand alone generators.

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From normative influence to social pressure: how relevant others affect whether bystanders join in cyberbullying

As cyberbullying is a phenomenon that is inherently social, the normative social influence of significant others can play an important role in the behaviour of adolescents involved in cyberbullying incidents. Using data from 525 adolescent bystanders of cyberbullying, we created a path model in order to investigate whether injunctive and descriptive norms of certain reference groups can cause bystanders to experience social pressure and join in cyberbullying. The results showed that social pressure fully mediated the relationship between the injunctive norm of friends approving of cyberbullying and joining in cyberbullying as a bystander. Furthermore, both the injunctive norm of parents approving of cyberbullying and bystanders' involvement in cyberbullying perpetration were related to joining in cyberbullying as a bystander.

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Equating accelerometer estimates among youth: the Rosetta Stone 2

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'Can I afford to help?’: how affordances of communication modalities guide bystanders' helping intentions towards harassment on social network sites

When bystanders want to help victims of harassment on social network sites, they can be guided by the affordances of different communication modalities in order to make a communicative choice. Elaborating on the data of a previous experimental study with 453 adolescents, we compared bystanders' behavioural intentions to help the victim according to their 'mediacy' (via communication technologies (CT) or face-to-face) and their 'privacy' (in public or in private). Furthermore, we investigated whether the context of the harassing incident (incident severity, identity and behaviour of other bystanders) influenced the 'mediacy' and 'privacy' of bystanders' helping intentions. The results showed that in general bystanders had higher behavioural intentions to help the victim in private (vs. in public) and via CT (vs. face-to-face). While incident severity influenced the 'mediacy' of bystanders' helping intentions, the identity and behaviour of other bystanders affected the 'privacy' of their helping intentions.

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Micro-architecture independent branch behavior modeling

In this paper, we propose linear branch entropy, a new metric for characterizing branch behavior. The metric is independent of the configuration of a specific branch predictor, but it is highly correlated with the branch miss rate of any predictor. In particular, we show that there is a linear relationship between linear branch entropy and the branch miss rate. This means that the metric can be used to estimate branch miss rates without simulating a branch predictor by constructing a linear function between entropy and miss rate. The resulting model is more accurate than previously proposed branch classification models, such as taken rate and transition rate. Furthermore, linear branch entropy can be used to analyze the branch behavior of applications, independent of specific branch predictor implementations, and the linear branch miss rate function enables comparing branch predictors on how well they perform on easy-to-predict versus hard-to-predict branches. As a case study, we find that the winner of the latest branch predictor competition performs worse on hard-to-predict branches, compared to the third runner-up; however, since the benchmark suite mainly consisted of easy branches, a predictor that performs well on easy-to-predict branches has a lower average miss rate.

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Measuring dwell time percentage from head-mounted eye-tracking data: comparison of a frame-by-frame and a fixation-by-fixation analysis

Although analysing software for eye-tracking data has significantly improved in the past decades, the analysis of gaze behaviour recorded with head-mounted devices is still challenging and time-consuming. Therefore, new methods have to be tested to reduce the analysis workload while maintaining accuracy and reliability. In this article, dwell time percentages to six areas of interest (AOIs), of six participants cycling on four different roads, were analysed both frame-by-frame and in a 'fixation-by-fixation' manner. The fixation-based method is similar to the classic frame-by-frame method but instead of assigning frames, fixations are assigned to one of the AOIs. Although some considerable differences were found between the two methods, a Pearson correlation of 0.930 points out a good validity of the fixation-by-fixation method. For the analysis of gaze behaviour over an extended period of time, the fixation-based approach is a valuable and time-saving alternative for the classic frame-by-frame analysis.

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Concept study of a double rotor induction machine used as continuously variable transmission

In a drive train a continuously variable transmission (CVT) has the advantage that the combustion engine can be driven in its optimal point along the requested power curve, which enhances overall efficiency. Moreover there is no power loss during shifting of gears which is often demanded in off highway applications. Several mechanical and hydraulic CVT's exist that have already proven their functionality, each having their pros and cons. This paper introduces the concept of an electromagnetic CVT which has some inherent advantages compared to mechanical systems being the absence of friction and the need for lubrication, only two moving parts and inherent overload protection. The machine can be seen as a conventional induction motor with two rotors. The rotors are arranged in a concentric way and are electromagnetically coupled. The working principle is explained, and an efficiency map is calculated for a scaled test case. It is concluded that with a smart choice of the interrotor flux a good efficiency can be achieved in a broad range of torque and flux of the interrotor.

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Development and usability of a computer-tailored pedometer-based physical activity advice for breast cancer survivors

This observational study aimed to adapt a computer-tailored step advice for the general population into a feasible advice for breast cancer survivors and to test its usability. First, several adaptations were made to the original design (adding cancer-related physical activity (PA) barriers and beliefs, and self-management strategies to improve survivors' personal control). Second, the adapted advice was evaluated in two phases: (1) a usability testing in healthy women (n = 3) and survivors (n = 6); and (2) a process evaluation during 3 weeks in breast cancer survivors (n = 8). Preliminary usability testing revealed no problems during logging-in; however, three survivors misinterpreted some questions. After refining the questionnaire and advice, survivors evaluated the advice as interesting, attractive to read, comprehensible and credible. Inactive survivors found the advice novel, but too long. The process evaluation indicated that the majority of the women (n = 5/8) reported increased steps. Monitoring step counts by using a pedometer was perceived as an important motivator to be more active. To conclude, this study provides initial support for the usability and acceptability of a computer-tailored pedometer-based PA advice for breast cancer survivors. After testing efficacy and effectiveness of this intervention, this tool can broaden the reach of PA promotion in breast cancer survivors.

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The effect of a reduced power quality on the energy efficiency of stand-alone generator systems

It has already been thoroughly validated that the efficiency of direct online motors is susceptible towards certain power quality parameters such as voltage unbalance or harmonic voltage distortion. It can be assumed that electrical generators are also susceptible to these parameters, but to the author's knowledge this effect has not yet been evaluated in scientific studies. This paper starts from the well studied additional loss mechanisms inside induction motors and consequently efforts are presented to translate these effects to stand-alone synchronous generators. Subsequently, the paper presents extensive measurements related to the effect of unbalanced and non-linear loading on the energy efficiency of 2 different 4kVA stand alone generators.

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Plasma microRNA biomarker detection for mild cognitive impairment using differential correlation analysis

Background: Mild cognitive impairment (MCI) is an intermediate state between normal aging and dementia including Alzheimer's disease. Early detection of dementia, and MCI, is a crucial issue in terms of secondary prevention. Blood biomarker detection is a possible way for early detection of MCI. Although disease biomarkers are detected by, in general, using single molecular analysis such as t-test, another possible approach is based on interaction between molecules. Results: Differential correlation analysis, which detects difference on correlation of two variables in case/control study, was carried out to plasma microRNA (miRNA) expression profiles of 30 age- and race-matched controls and 23 Japanese MCI patients. The 20 pairs of miRNAs, which consist of 20 miRNAs, were selected as MCI markers. Two pairs of miRNAs (hsa-miR-191 and hsa-miR-101, and hsa-miR-103 and hsa-miR-222) out of 20 attained the highest area under the curve (AUC) value of 0.962 for MCI detection. Other two miRNA pairs that include hsa-miR-191 and hsa-miR-125b also attained high AUC value of ≥ 0.95. Pathway analysis was performed to the MCI markers for further understanding of biological implications. As a result, collapsed correlation on hsa-miR-191 and emerged correlation on hsa-miR-125b might have key role in MCI and dementia progression. Conclusion: Differential correlation analysis, a bioinformatics tool to elucidate complicated and interdependent biological systems behind diseases, detects effective MCI markers that cannot be found by single molecule analysis such as t-test.

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Videotaping of surgical procedures and outcomes following extraperitoneal laparoscopic radical prostatectomy for clinically localized prostate cancer

Background

Video-recording of emerging minimally invasive surgical procedures is likely to become an integral component of patient record-keeping in the future for prostate cancer treatment. No prior work has shown the impact of videotaping of laparoscopic prostatectomy on patient outcomes. Our aim was to determine correlation between independent peer review of videotaping quality scores of extraperitoneal laparoscopic prostatectomy (ELRP) with complications, re-admissions, functional, and early oncological outcomes.

Study Design, Setting, and Participants

We conducted a single-institution prospective cohort study comparing videotaping quality scores with the outcomes of ELRP in men with localized prostate cancer. Videotaping of surgical procedures were scored by two experienced laparoscopic surgeons using a validated scoring method. Validated record-linkage methodology and self-reported questionnaires were used to assess surgical complications, re-admissions, functional, and oncological outcomes based on a common identifier called as community health index (CHI) number. Pearson correlation coefficients were calculated between the different covariates with statistical significance considered at P < 0.05. Multivariate analyses assessed oncological outcomes (positive surgical margins/biochemical recurrence), post-operative complications, and re-admission into hospital following initial hospital discharge with quality of surgical procedure.

Results

200 men were recruited into the study. 51 (25.5%) participants had post-operative complications. Record-linkage methodology identified 18 (9%) participants had re-admissions within 90 days of the procedure. 13 (6.5%) of these men required percutaneous drainage with hospital stay following re-admissions ranged between 3 and 12 days. 10 (5.0%) participants had intra/peri-operative complications. 23 (11.5%) men reported to primary care physicians for various indications. Higher quality surgical technique videotaped scores (assessed by independent peer review) had a significant correlation with early continence recovery at 3 months post-procedure, (P = 0.013), but lost statistical significance with overall continence at 1 year. No statistical correlation was observed between videotaped scores and oncological outcomes (positive surgical margins/biochemical recurrence), post-operative complications, and readmission into hospital.

Conclusions

Quality of surgical procedure assessed by independent third party videotaping score predicted early resumption of continence following extraperitoenal laparoscopic radical prostatectomy, however, it did not predict complications, oncological or functional outcome as assessed using patient reported outcomes at 12 months. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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Latissimus dorsi flap with vascularized lymph node transfer for lymphedema treatment: Technique, outcomes, indications and review of literature

Background and Objectives

One of the surgical treatment options for lymphedema is vascularized lymph node transfer (VLNT). We present our experience with latissimus dorsi (LD) flap based VLNT for lymphedema treatment.

Methods

We reviewed 14 consecutive patients treated with pedicled or free LD VLNT between 2014 and 2016 for recalcitrant upper or lower extremity lymphedema. Seven patients underwent lymphovenous bypass in addition to LD VLNT. Limb volume and quality of life scores using the Lymphedema Life Impact Scale (LLIS) were analyzed for quantitative and qualitative assessment.

Results

Mean duration of lymphedema was 69 months (range 24–124 months). Follow-up ranged from 3 to 12 months (mean 6.7 month). Major complications included one free flap loss and one reoperation for thrombosis. Mean preoperative volume differential between normal and affected limb was 35% (range 3–87%). Volume differential reduction was 48%, 28%, and 46% at 3, 6, and 12 months, respectively. The LLIS score improved from mean of 46.8 before surgery to a mean of 38.6 at 12 month, demonstrating improvement in quality of life.

Conclusions

The LD VLNT provides a viable option for treatment of UE and LE lymphedema in selected patients. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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Cover Image, Volume 36, Issue 12

Prenatal ultrasonography of the third fetus at 16 gestational weeks showing multiple joint contractures (arthrogryposis). From Chen et al., Prenat Diagn 36: 1135-1138, DOI: 10.1002/pd.4949

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Issue Information

No abstract is available for this article.

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Proliferation-Related Activity in Endothelial Cells Is Enhanced by Micropower Plasma

Nonthermal plasma has received a lot of attention as a medical treatment technique in recent years. It can easily create various reactive chemical species (ROS) and is harmless to living body. Although plasma at gas-liquid interface has a potential for a biomedical application, the interactions between the gas-liquid plasma and living cells remain unclear. Here, we show characteristics of a micropower plasma with 0.018 W of the power input, generated at gas-liquid interface. We also provide the evidence of plasma-induced enhancement in proliferation activity of endothelial cells. The plasma produced H2O2, HNO2, and HNO3 in phosphate buffered saline containing Mg++ and Ca++ (PBS(+)), and their concentration increased linearly during 600-second discharge. The value of pH in PBS(+) against the plasma discharge time was stable at about 7.0. Temperature in PBS(+) rose monotonically, and its rise was up to 0.8°C at the bottom of a cell-cultured dish by the plasma discharge for 600 s. Short-time treatment of the plasma enhanced proliferation activity of endothelial cells. In contrast, the treatment of H2O2 does not enhance the cell proliferation. Thus, the ROS production and the nuclear factor-kappa B (NF-κB) activation due to the plasma treatment might be related to enhancement of the cell proliferation. Our results may potentially provide the basis for developing the biomedical applications using the gas-liquid plasma.

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New tool to help predict dementia risk in older people

Preventing dementia is a major public health priority worldwide, and intense work is being conducted to formulate effective preventive strategies. Healthy lifestyle changes may help prevent cognitive decline and dementia, but the challenge is to detect early on those who are most at risk and to choose the most relevant preventive measures.

Recent developments in dementia prevention research include large online Brain Health Registries, multinational data discovery and sharing platforms, and internet-based prevention trials. Dealing with large amounts of health information – "big data"– is a challenging consequence of these developments. Machine learning represents a type of artificial intelligence where a group of methods is used to teach computers to make and improve predictions based on large datasets. These methods are just starting to be used in the context of dementia prevention.

A team of medical doctors and engineers from Finland and Sweden addressed these challenges using a novel machine learning approach. They developed a dementia risk index – a tool for assessing people's risk of dementia and for indicating the most relevant target areas for preventive measures. An added advantage of the tool is the ability to show detailed individual dementia risk profiles in a visual format that is easy to interpret.

Risk index predicted dementia ten years before onset

The research team used data from the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study conducted in Eastern Finland. Study participants were cognitively normal individuals aged 65-79 years from the general Finnish population who underwent detailed health-related assessments, including memory and other cognitive tests. The dementia risk index performed well in identifying comprehensive profiles for predicting dementia development up to 10 years later. The main included predictors were cognition, vascular factors, age, subjective memory complaints and apolipoprotein E (APOE) genotype.

The researchers conclude that the risk index could be useful for identifying older individuals who are most at risk, and who may also benefit most from preventive interventions. They emphasize that the risk index is not meant for dementia diagnosis, but as a tool to help with making decisions about dementia prevention strategies, i.e. to whom these should be targeted, and what risk factors should be specifically addressed based on the visual risk profile.

"The results of our study are very promising, as it is the first time this machine learning approach was used for estimating dementia risk in a cognitively normal general population," says the lead researcher, Alina Solomon, MD, PhD, from the University of Eastern Finland.

"The risk index was designed to support clinical decision making, and we are very keen on exploring its potential practical use. However, we still need to validate this risk index in other populations outside Finland. We also need to investigate if it works in people older than 80 years, and if it can monitor changes in dementia risk over time, for example as a response to lifestyle interventions. These are some of the next steps we are planning now," Dr Solomon adds.

"Large health information databases contain a lot of valuable information which is still partly hidden and under-exploited. Modern machine learning methods can be used to extract patterns of data that may be difficult to observe just by looking at the data by eye. Our objective has been to detect patterns that predict whether a person is more likely to get dementia in the future. Another area of interest has been how to present all these complex data in a simple form to make these modern technologies useful for clinicians and general public interested in dementia prevention", says Jyrki Lötjönen, PhD, one of the co-authors in the study and chief scientific officer at Combinostics Ltd. 

The study was funded by the European Union 7th Framework Programme via the VPH-DARE@IT project; Academy of Finland, Swedish Research Council and EU Joint Programme – Neurodegenerative Disease Research (JPND); the strategic funding of the University of Eastern Finland via the UEF-BRAIN consortium; Swedish Center for Innovative Medicine (CIMED), Sweden; Alzheimerfonden Sweden; and AXA Research Fund.

Pekkala T, Hall A, Lötjönen J, Mattila J, Soininen H, Ngandu T, Laatikainen T, Kivipelto M, Solomon A. Development of a Late-Life Dementia Prediction Index with Supervised Machine Learning in the Population-Based CAIDE Study. J Alzheimers Dis. 2016 Oct 14. [Epub ahead of print].

ABOUT THE JOURNAL OF ALZHEIMER'S DISEASE (JAD)
The Journal of Alzheimer's Disease is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment, and psychology of Alzheimer's disease. The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. Groundbreaking research that has appeared in the journal includes novel therapeutic targets, mechanisms of disease and clinical trial outcomes. The Journal of Alzheimer's Disease has an Impact Factor of 3.920 according to Thomson Reuters' 2015 Journal Citation Reports. The Journal is published by IOS Press. 

For further information, please contact:
Alina Solomon, MD, PhD, University of Eastern Finland, Institute of Clinical Medicine, Neurology, +358 40 3552 015, email alina.solomon@uef.fi.

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Noise-Corrected Principal Component Analysis of fluorescence lifetime imaging data

Fluorescence Lifetime Imaging (FLIM) is an attractive microscopy method in the life sciences, yielding information on the sample otherwise unavailable through intensity-based techniques. A novel Noise-Corrected Principal Component Analysis (NC-PCA) method for time-domain FLIM data is presented here. The presence and distribution of distinct microenvironments are identified at lower photon counts than previously reported, without requiring prior knowledge of their number or of the dye's decay kinetics. A noise correction based on the Poisson statistics inherent to Time-Correlated Single Photon Counting is incorporated. The approach is validated using simulated data, and further applied to experimental FLIM data of HeLa cells stained with membrane dye di-4-ANEPPDHQ. Two distinct lipid phases were resolved in the cell membranes, and the modification of the order parameters of the plasma membrane during cholesterol depletion was also detected.

The presence and distribution of multiple fluorescent emitting species are resolved in Fluorescence Lifetime Imaging data using NC-PCA, a Principal Component Analysis tailored for single photon counting through a Poisson noise correction. NC-PCA allows sensitive resolution in low intensity situations characteristic of live cell imaging, and prior knowledge of the photophysics of the system is not required.

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Objective identification of dental abnormalities with multispectral fluorescence imaging

Sensitive methods that can enable early detection of dental diseases (caries and calculus) are desirable in clinical practice. Optical spectroscopic approaches have emerged as promising alternatives owing to their wealth of molecular information and lack of sample preparation requirements. In the present study, using multispectral fluorescence imaging, we have demonstrated that dental caries and calculus can be objectively identified on extracted tooth. Spectral differences among control, carious and calculus conditions were attributed to the porphyrin pigment content, which is a byproduct of bacterial metabolism. Spectral maps generated using different porphyrin bands offer important clues to the spread of bacterial infection. Statistically significant differences utilizing fluorescence intensity ratios were observed among three groups. In contrast to laser induced fluorescence, these methods can provide information about exact spread of the infection and may aid in long term dental monitoring. Successful adoption of this approach for routine clinical usage can assist dentists in implementing timely remedial measures.

The reliance on examiner experience rather than on quantifiable biomarkers has often been associated with poor diagnostic certainty and overtreatment of dental diseases. Here we present first report of multispectral fluorescence imaging for diagnosis of dental diseases. This can provide real-time, wide-field chemical information, enabling improved diagnostic capabilities reducing the well documented risks, costs, and psychological effects that result from incorrect diagnosis.

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Abdominal Wall Reconstruction Using Retrorectus Self-adhering Mesh: A Novel Approach

Background: In abdominal wall reconstruction, the retrorectus plane offers an ideal location for mesh placement. Mesh fixation in this plane is often achieved using transfascial sutures, which risks entrapping intercostal nerves and causing significant pain, and takes time to place. A novel alternative is the use of sutureless self-adhering mesh. Although the use of this mesh in inguinal hernias has been well described, studies on its use in abdominal wall reconstruction are lacking. Methods: Consecutive patients who underwent ventral hernia repair with retrorectus mesh were reviewed. This included patients who received transfascially sutured mesh and those who received sutureless self-adhering mesh. All patients were followed up for at least 12 months. The amount of narcotics required by each patient postoperatively was calculated. Surgical-site occurrences (SSOs) and hernia recurrence and bulge were measured. Results: Twenty-six patients underwent abdominal wall reconstruction with retrorectus mesh. This included 12 patients with transfascially sutured mesh and 14 patients with self-adhering mesh. Mean follow-up was 600 days. Baseline characteristics were similar between the 2 groups. Patients receiving self-adhering mesh required significantly less narcotics than patients with transfascially sutured mesh. There were no significant differences in the rate of SSOs between the 2 groups. No hernia recurrences, bulges, or chronic pain occurred in either group. Conclusions: This is the first study to compare the outcomes of retrorectus self-adhering mesh and transfascially sutured mesh in abdominal wall reconstruction. Our results show low rates of SSO, recurrence, and bulge with both options, with significantly less acute pain with self-adhering mesh.

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The Nipple–Areola Preserving Mastectomy: The Value of Adding a Delay Procedure

Background: Conservative mastectomy procedures, such as the nipple-sparing mastectomy (NSM), present appealing options for patients with small invasive or noninvasive malignancies and those needing prophylactic mastectomies. Despite outstanding postoperative cosmetic results, nipple–areola complex (NAC) and mastectomy skin flap (MSF) survival remains a concern. We present our two-stage nipple–areola preserving (NAP) mastectomy, which aims to decrease the rate of NAC loss and MSF necrosis after conservative mastectomies. Material and Methods: Seventy patients who underwent NSM because of malignant and benign conditions were divided into 2 groups: those who underwent our two-stage NAP mastectomy were matched to the group of mastectomy patients without preservation techniques. Demographic data and postoperative results were retrospectively assessed. Results: The NAP group comprised 45 flaps (24 patients), and the NSM group comprised 75 flaps (46 patients). None were actively smoking. The mean time between the delay of the flap and breast reconstruction was 17.6 days (range, of 10–35 days) in the NAP group. No signs of NAC vascular compromise were observed in the NAP group. Nipple necrosis rates were significantly greater (P = 0.0136) in the NSM group: 9 cases in the NSM group versus none within the NAP group. Two patients within the NAP group required nipple excision at the time of their mastectomies after biopsies performed at the time of the NAC delay were positive for malignancy or atypia. Conclusions: Vascular delay techniques favor the blood supply of a tissue after a surgical wound, effectively improving the survival of the NAC and MSF after nipple-sparing mastectomies.

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Verification of aggregated flows in OpenFlow networks

Recently, the automatic test packet generation (ATPG) tool is proposed to verify a network for error conditions (e.g., incorrect firewall rules, software, hardware, and performance errors). However, this tool is not able to verify aggregated flows (i.e., flows having wildcards in some of their fields) for matching issues. In this paper, we propose a mechanism to verify aggregated flows in OpenFlow networks. In the demonstration, we verify aggregated flows installed in an emulated pan-European topology using our proposed mechanism.

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The effect of relaxation therapy on autonomic functioning, symptoms and daily functioning, in patients with chronic fatigue syndrome or fibromyalgia: a systematic review

Objective: To establish the effects of relaxation therapy on autonomic function, pain, fatigue and daily functioning in patients with chronic fatigue syndrome or fibromyalgia. Method: A systematic literature study was performed. Using specific keywords related to fibromyalgia or chronic fatigue syndrome and relaxation therapy, the electronic databases PubMed and Web of Science were searched. Included articles were assessed for their risk of bias and relevant information regarding relaxation was extracted. The review was conducted and reported according to the PRISMA-statement. Results: Thirteen randomized clinical trials of sufficient quality were included, resulting in a total of 650 fibromyalgia patients (11 studies) and 88 chronic fatigue syndrome patients (3 studies). None of the studies reported effects on autonomic function. Six studies reported the effect of guided imagery on pain and daily functioning in fibromyalgia. The acute effect of a single session of guided imagery was studied in two studies and seems beneficial for pain relief. For other relaxation techniques (eg. muscle relaxation, autogenic training) no conclusive evidence was found for the effect on pain and functioning in fibromyalgia patients comparison to multimodal treatment programs. For fatigue a multimodal approach seemed better than relaxation, as shown in the sole three studies on chronic fatigue syndrome patients. Conclusion: There is moderate evidence for the acute effect of guided imagery on pain, although the content of the visualization is a matter of debate. Other relaxation formats and the effects on functionality and autonomic function require further study.

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