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This study aims to understand the impact of the overall charge of Fe(III) chelates on their water exchange kinetics, thermodynamic stability, and kinetic inertia. To this end, we synthesized two CDTA‐amide ligands, each characterized by the replacement of one or two carboxyl groups with diethylamide functionalities. These alterations produced Fe(III) complexes with neutral or positively charged characteristics. The rate of water exchange (kex) was determined through a combined analysis of 1H relaxometric data and 1⁷O NMR chemical shift and transverse relaxation rate data. Additionally, we evaluated the thermodynamic stability and kinetic inertness of the complexes using potentiometry, UV‐Vis spectrophotometry, and capillary zone electrophoresis. Our results indicate that altering the charge of the complex slows down kex, consistent with previous observations for Gd(III) and Mn(II) chelates. Furthermore, the results indicate that incorporating amide donor groups decreases the stability of the complexes and reduces their kinetic inertia. However, both stability and kinetic inertia remain higher than those of [Fe(EDTA)]−. These findings provide some valuable insights for the development of Fe(III)‐based MRI probes alternative to those based on Gd(III). [ABSTRACT FROM AUTHOR]

Background and Objective: Several randomized controlled trials (RCTs) have shown that benralizumab is characterized by a good profile of efficacy and safety, thereby being potentially able to elicit clinical remission on‐treatment of severe eosinophilic asthma (SEA). The main goal of this multicentre observational study was to verify the effectiveness of benralizumab in inducing a sustained remission on‐treatment of SEA in patients with or without comorbid chronic rhinosinusitis with nasal polyps (CRSwNP). Methods: Throughout 2 years of treatment with benralizumab, a four‐component evaluation of sustained remission of SEA was performed, including the assessment of SEA exacerbations, use of oral corticosteroids (OCSs), symptom control and lung function. Results: The present study recruited 164 patients suffering from SEA. After 24 months of add‐on biological therapy with benralizumab, 69 (42.1%) achieved the important target of sustained remission on‐treatment (exacerbation rate = 0, OCS dose = 0, pre‐bronchodilator FEV1 ≥80% pred., ACT score ≥ 20). During the same period, a persistent improvement of CRSwNP (SNOT‐22 < 30, NP recurrence = 0) was observed in 33 (40.2%) out of 82 subjects with concomitant NP. The latter comorbidity and post‐bronchodilator reversibility of airflow limitation were two independent predictors of sustained remission on‐treatment (OR = 2.32, p < 0.05 and OR = 5.59, p < 0.01, respectively). Conclusion: Taken together, the results of this real‐life clinical investigation indicate that benralizumab can induce a sustained remission on‐treatment of SEA, especially in those patients with comorbid CRSwNP and reversible airflow limitation. [ABSTRACT FROM AUTHOR]

Inflammation is a common condition of prostate tissue, whose impact on carcinogenesis is highly debated. Microbial colonization is a well-documented cause of a small percentage of prostatitis cases, but it remains unclear what underlies the majority of sterile inflammation reported. Here, androgen- independent fluctuations of PSA expression in prostate cells have lead us to identify a prominent function of the Transient Receptor Potential Cation Channel Subfamily M Member 8 (TRPM8) gene in sterile inflammation. Prostate cells secret TRPM8 RNA into extracellular vesicles (EVs), which primes TLR3/NF-kB-mediated inflammatory signaling after EV endocytosis by epithelial cancer cells. Furthermore, prostate cancer xenografts expressing a translation-defective form of TRPM8 RNA contain less collagen type I in the extracellular matrix, significantly more infiltrating NK cells, and larger necrotic areas as compared to control xenografts. These findings imply sustained, androgen-independent expression of TRPM8 constitutes as a promoter of anticancer innate immunity, which may constitute a clinically relevant condition affecting prostate cancer prognosis. Synopsis: The molecular origins of chronic tissue inflammation and its impact on cancer growth remain elusive. This study identifies TRPM8 transcripts as androgen-independent driver of sterile inflammation in the prostate gland, promoting anticancer innate immunity in the tumor microenvironment. TRPM8 RNA is secreted via extracellular vesicles (EVs) by normal and prostate cancer cells in the absence of cell damage. Upon EV endocytosis, TRPM8 mRNA binds TLR3 in endosomes, thereby promoting NF-kB/IRF3 activation and release of pro-inflammatory signals. NF-kB induces the androgen-independent expression of PSA encoded by the KLK3 gene. TRPM8/TLR3 signaling induces inflammation in prostate cancer xenografts, promoting infiltration and anticancer activity of NK cells. TLR3-activation by extracellular vesicle-delivered TRPM8 mRNA triggers aseptic inflammation in the prostate epithelium, promoting tumor suppression by NK cells. [ABSTRACT FROM AUTHOR]

Early diagnosis and efficient treatments of oncological, neurological, inflammatory, and infectious diseases rely more and more on ultrasensitive detection of protein markers; the ultimate limit is a reliable immunoassay capable of single‐protein detection. Among protein biomarkers, cytokines play a key role in clinical diagnosis as they are involved in developing many complex diseases and disorders, such as chronic inflammatory diseases including metabolic syndrome, neurodegenerative diseases, and cardiovascular diseases, along with autoimmune diseases and cancer. Herein, the improvement of a Single Molecule with Transistor (SiMoT) is reported based on an electrolyte‐gated organic field‐effect transistor applied for the detection of cytokine IL‐6 in blood serum, reaching a limit‐of‐detection (LOD) of 1 ± 1 protein in a sample of 0.1 mL. The analytical performance levels are benchmarked against the Simoa Planar Array SP‐X technology, a benchtop chemiluminescent array. After comprehensive optimization, Simoa SP‐X by using a multivariate experimental design approach exhibits a LOD 103 higher than SiMoT. The proposed SiMoT electronic assay is label‐free, fast (30 min), and selective, paving the way for an ultra‐sensitive point‐of‐care immunoassay platform enabling pre‐symptomatic disease diagnosis. [ABSTRACT FROM AUTHOR]

The review discloses the historical and technological evolution of enzyme‐based field‐effect transistors (EnFETs) underlying the importance of gate electrode modification toward the implementation of novel FETs configurations such as extended‐gate FET (EG‐FETs) or EG organic FETs (EG‐OFETs). The working principle of the EnFETs as postulated by Bergveld in 1970, who defined the EnFET as an ion‐selective FET (ISFET) modified with enzyme‐membrane, is also discussed considering the analytical equations related to the EnFET output response. For each category, namely EnFETs, EG‐FETs, and EG‐OFETs, we reviewed the key devices' configurations that addressed the research in this field in the last 40 years with particular attention to the analytical figures of merit. [ABSTRACT FROM AUTHOR]

Lysosomal storage diseases (LSDs) are rare genetic metabolic disorders that cause the accumulation of glycosaminoglycans in lysosomes due to enzyme deficiency or reduced function. Enzyme replacement therapy (ERT) represents the gold standard treatment, but hypersensitivity reaction can occur resulting in treatment discontinuation. Thus, desensitization procedures for different culprit recombinant enzymes can be performed to restore ERT. We searched desensitization procedures performed in LSDs and focused on skin test results, protocols and premedication performed, and breakthrough reactions occurred during infusions. Fifty‐two patients have been subjected to desensitization procedures successfully. Skin tests, with the culprit recombinant enzyme, deemed positive in 29 cases, doubtful in two cases, and not performed in four patients. Moreover, 29 of the 52 desensitization protocols used at the first infusion were breakthrough reaction free. Different desensitization strategies have proved safe and effective in restoring ERT in patients with previous hypersensitivity reactions. Most of these events seem to be Type I hypersensitivity reactions (IgE‐mediated). Standardized in vivo and in vitro testing is necessary to better estimate the risk of the procedure and find the safest individualized desensitization protocol. [ABSTRACT FROM AUTHOR]

Nonrandomized studies (NRS) on allergen immunotherapy (AIT) particularly lend themselves to evaluate outcomes that are insufficiently addressed in randomized controlled studies (RCTs). However, NRS are prone to several sources of bias, which limit their validity. We aimed at comparing AIT effects between RCTs and NRS and evaluate the reasons for discrepancies in study results. In this analysis, we compared NRS on AIT (including subcutaneous and sublingual immunotherapy, SCIT and SLIT, respectively) with SLIT and SCIT RCTs from published meta‐analyses, assessing the Risk of Bias (RoB) for each study and the certainty of evidence from NRS and RCTs using the GRADE approach. We found: (1) very serious RoB in the 7 NRS included in the meta‐analysis showing a large difference between AIT and controls (standardized mean difference [SMD] for symptom score [SS], −1.77; 95% CI, −2.30, −1.24; p <.001; I2 = 95%) with very low certainty evidence; (2) serious RoB in the 13 SCIT‐RCTs reporting a moderate‐to‐high difference between SCIT and controls (SMD for SS, −0.81; 95% CI, −1.12, −0.49; p <.001; I2 = 88%) with moderate certainty evidence; (3) low RoB in the 13 SLIT‐RCTs reporting a small benefit (SMD for SS, −0.28; 95% CI, −0.37, −0.19; p <.001; I2 = 54.2%) with high certainty evidence. Similar results were reported for medication score. Our evidence is sufficient to conclude that the magnitude of effect estimates of NRS and RCTs directly correlate with the degree of RoB and inversely with the overall evidence certainty. NRS, which are more affected than RCTs by bias resulting in low certainty evidence, showed the largest effect size. Sound NRS are needed to complement RCTs. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the reproducibility and stability of left breast positioning during spirometer‐guided deep‐inspiration breath‐hold (DIBH) radiotherapy using an optical surface imaging system (AlignRT). The AlignRT optical tracking system was used to monitor five left‐sided breast cancer patients treated using the Active Breathing Coordinator spirometer with DIBH technique. Treatment plans were created using an automated hybrid‐VMAT technique on DIBH CTs. A prescribed dose of 60 Gy to the tumor bed and 50 Gy to the breast in 25 fractions was planned. During each treatment session, the antero‐posterior (VRT), superior‐inferior (LNG), and lateral (LAT) motion of patients was continuously recorded by AlignRT. The intra‐breath‐hold stability and the intra‐ and inter‐fraction reproducibility were analyzed for all breath‐holds and treatment fractions. The dosimetric impact of the residual motion during DIBH was evaluated from the isocenter shifts amplitudes obtained from the 50%, 90%, and 100% cumulative distribution functions of intra‐fractional reproducibility. The positional variations of 590 breath‐holds as measured by AlignRT were evaluated. The mean intra‐breath‐hold stability during DIBH was 1.0 ± 0.4 mm, 2.1 ± 1.9 mm, and 0.7 ± 0.5 mm in the VRT, LNG, and LAT directions, with a maximal value of 8.8 mm in LNG direction. Similarly, the mean intra‐breath‐hold reproducibility was 1.4 ± 0.8 mm, 1.7 ± 1.0 mm, and 0.8 ± 0.5 mm in the VRT, LNG, and LAT directions, with a maximal value of 4.1 mm in LNG direction. Inter‐fractional reproducibility showed better reliability, with difference in breathing levels in all fractions of 0.3 mm on average. Based on tolerance limits corresponding to the 90% cumulative distribution level, gating window widths of 1 mm, 2 mm, and 5 mm in the LAT, VRT, and LNG directions were considered an appropriate choice. In conclusion, despite the use of a dedicated spirometer at constant tidal volume, a non‐negligible variability of the breast surface position has been reported during breath‐holds. The real‐time monitoring of breast surface using surface‐guided optical technology is strongly recommended. [ABSTRACT FROM AUTHOR]

A plethora of different electronic and optoelectronic devices have been developed lately, for biosensing applications (e.g., label‐free, fast, and easier to operate) based on a detecting interface accommodating the biorecognition elements, anchored by thiolate self‐assembled monolayers (SAMs) on a gold surface. Here, a surface plasmon resonance (SPR) characterization of anti‐p24 anchored on different SAMs is performed to investigate the effect of the SAM structure on the antibodies' packing efficiency and the sensors' analytical figures of merit. Notably, the mixed SAM deposited from a solution 10:1 of 3‐mercaptopropionic acid and 11‐mercaptoundecanoic acid (11MUA) is compared to that resulting from a solution 10:1 of ad hoc synthesized N‐(2‐hydroxyethyl)‐3‐mercaptopropanamide (NMPA)/11MUA. Despite the improvement in the anti‐p24 surface coverage registered using the 11MUA/NMPA SAM, the latter produces a significant decrease in the antibodies' binding efficiency against human immunodeficiency virus p24 protein. To provide a molecular rationale behind the SPR data, density functional theory calculations are also undertaken. A comprehensive physical view of the main competing phenomena affecting the biorecognition events at a biofunctionalized gold detecting interface is represented here. [ABSTRACT FROM AUTHOR]

This review discloses the technological advances involving enzyme‐based amperometric biosensors engaging challenging limits of detection as low as a single molecule. At first, we summarise the most recent findings concerning electrode modification toward the enhancement of the enzyme loading accomplished mainly through the deposition of nanomaterials. The increase of the electron transfer (ET) rate is mostly based on the enzyme site‐specific immobilization through the analysis of the enzyme structure/sequence and protein bioengineering is overviewed. However, both approaches are not appropriate to develop enzyme‐based amperometric biosensors able to reach reliable analytical detections below micro‐/nano‐molar. The last part is devoted to single‐molecule electrochemistry that has been widely exploited as a near‐field approach in the last decades as a proof‐of‐concept for the detection of single ET events. Organic electrochemical transistors operated as Faradaic current amplifiers do not detect below micro‐/nano‐molar. We here propose an alternative approach based on the combination of an electrochemical cell with a bipolar junction transistor in the extended base configuration, drawing some conclusions and future perspectives on the detection of single ET events at a large electrode for the development of Point‐of‐Care devices. [ABSTRACT FROM AUTHOR]

Few binding events are here shown to elicit an extended work function change in a large‐area Au‐surface biofunctionalized with ≈108 capturing antibodies. This is demonstrated by Kelvin probe force microscopy (KPFM), imaging a ≈105 µm2 wide Au‐electrodes covered by a dense layer (≈104 µm−2) of physisorbed anti‐immunoglobulin‐M (anti‐IgM). A 10 min incubation in 100 µL phosphate buffer saline solution encompassing ≈10 IgM antigens (10−19 mole L−1  102 × 10−21m) produces a work function shift ΔW ≈ –60 meV. KPFM images prove that this shift involves the whole inspected area. Notably, no work function change occurs upon incubation in highly concentrated (3 × 10−15m) nonbinding IgG solutions. The ΔW measured by KPFM is in quantitative agreement with the threshold voltage shift of an electrolyte‐gated single‐molecule large‐area transistor (SiMoT). The findings provide direct experimental evidence for the SiMoT ultrahigh sensitivity, by imaging the extensive shift of the gate work function, likely arising from collective surface phenomena, elicited by single‐molecule binding events. [ABSTRACT FROM AUTHOR]

Flavobacterium psychrophilum is the causative agent of bacterial cold‐water disease (CWBD) and rainbow trout fry syndrome (RTFS), which affect salmonids. To better understand this pathogen and its interaction with the host during infection, including to support the development of resistant breeds and new vaccines and treatments, there is a pressing need for reliable and reproducible immersion challenge models that more closely mimic natural routes of infection. The aim of this present study was to evaluate a challenge model developed previously for rainbow trout for use in Atlantic salmon. First, preliminary challenges were conducted in Atlantic salmon (n = 120) and rainbow trout (n = 80) fry using two F. psychrophilum isolates collected from each fish species, respectively; fish had been pretreated with 200 mg/L hydrogen peroxide for 1 h. Thereafter, the main challenge was performed for just one F. psychrophilum isolate for each species (at 2 × 107 CFU/mL) but using larger cohorts (Atlantic salmon: n = 1187; rainbow trout: n = 2701). Survival in the main challenge was 81.2% in Atlantic salmon (21 days post‐challenge) and 45.3% in rainbow trout (31 days post‐challenge). Mortalities progressed similarly during the preliminary and main challenges for both species, demonstrating the reproducibility of this model. This is the first immersion challenge model of F. psychrophilum to be developed successfully for Atlantic salmon. [ABSTRACT FROM AUTHOR]

Pathogens ultra‐sensitive detection is vital for early diagnosis and provision of restraining actions and/or treatments. Among plant pathogens, Xylella fastidiosa is among the most threatening as it can infect hundreds of plant species worldwide with consequences on agriculture and the environment. An electrolyte‐gated transistor is here demonstrated to detect X. fastidiosa at a limit‐of‐quantification (LOQ) of 2 ± 1 bacteria in 0.1 mL (20 colony‐forming‐unit per mL). The assay is carried out with a millimeter‐wide gate functionalized with Xylella‐capturing antibodies directly in saps recovered from naturally infected plants. The proposed platform is benchmarked against the quantitave polymerase chain reaction (qPCR) gold standard, whose LOQ turns out to be at least one order of magnitude higher. Furthermore, the assay selectivity is proven against the Paraburkholderia phytofirmans bacterium (negative‐control experiment). The proposed label‐free, fast (30 min), and precise (false‐negatives, false‐positives below 1%) electronic assay, lays the ground for an ultra‐high performing immunometric point‐of‐care platform potentially enabling large‐scale screening of asymptomatic plants. [ABSTRACT FROM AUTHOR]

Single‐molecule detection at a nanometric interface in a femtomolar solution, can take weeks as the encounter rate between the diffusing molecule to be detected and the transducing nanodevice is negligibly small. On the other hand, several experiments prove that macroscopic label‐free sensors based on field‐effect‐transistors, engaging micrometric or millimetric detecting interfaces are capable to assay a single‐molecule in a large volume within few minutes. The present work demonstrates why at least a single molecule out of a few diffusing in a 100 µL volume has a high probability to hit a large capturing and detecting electronic interface. To this end, sensing data, measured with an electrolyte‐gated FET whose gate is functionalized with 1012 capturing anti‐immunoglobulin G, are here provided along with a Brownian diffusion‐based modeling. The EG‐FET assays solutions down to some tens of zM in concentrations with volumes ranging from 25 µL to 1 mL in which the functionalized gates are incubated for times ranging from 30 s to 20 min. The high level of accordance between the experimental data and a model based on the Einstein's diffusion‐theory proves how the single‐molecule detection process at large‐capturing interfaces is controlled by Brownian diffusion and yet is highly probable and fast. [ABSTRACT FROM AUTHOR]

Background and Purpose: Recently, β‐adrenoceptor blockade has emerged as a potential strategy to inhibit melanoma growth. It remains to be ascertained whether β‐adrenoceptor stimulation by circulating catecholamines increases melanoma growth in mice. Experimental Approach B16F10 melanoma‐bearing mice were used to evaluate effects of adrenaline and specific adrenoceptor (AR) ligands on tumour volume. AR expression and effects of AR ligands on cell viability, production of mitochondrial reactive oxygen species (mROS), and proliferation activity in B16F10 cells, were determined by biochemical analyses. Key Results: Real‐time polymerase chain reaction (qPCR) analyses revealed that B16F10 cells express α1B‐, α2A‐, α2B‐ and β2‐ARs. We found that treatment with the α‐ and β‐AR agonist adrenaline or with the synthetic catecholamine isoprenaline, which selectively stimulates β‐ARs, did not affect melanoma growth. Conversely, adrenaline reduced tumour growth in mice cotreated with propranolol, a β1β2‐AR antagonist. Adrenaline had no effect in tumour‐bearing β1β2‐AR knockout mice, in which β1‐ and β2‐ARs are lacking, but it reduced tumour growth when co‐administered with propranolol suggesting that tumour β2‐ARs negatively regulate adrenaline antitumour activity. Additionally, we found that α1‐AR stimulation with cirazoline yielded a decrease in B16F10 melanoma size. These effects on melanoma growth were paralleled by reduced cell viability and proliferation activity as well as increased mROS production in α1‐AR‐stimulated B16F10 cells. Decreased viability, proliferation and mitochondrial function in B16F10 cells also occurred after α2‐AR stimulation by α2‐AR agonist ST91. Conclusions and Implications: In the B16F10 melanoma model, stimulation of α‐AR subtypes yields in vivo and in vitro anticancer activity. [ABSTRACT FROM AUTHOR]

The SARS‐CoV‐2 main protease (Mpro) has a pivotal role in mediating viral genome replication and transcription of the coronavirus, making it a promising target for drugs against the COVID‐19 pandemic. Here, a crystal structure is presented in which Mpro adopts an inactive state that has never been observed before, called new‐inactive. It is shown that the oxyanion loop, which is involved in substrate recognition and enzymatic activity, adopts a new catalytically incompetent conformation and that many of the key interactions of the active conformation of the enzyme around the active site are lost. Solvation/desolvation energetic contributions play an important role in the transition from the inactive to the active state, with Phe140 moving from an exposed to a buried environment and Asn142 moving from a buried environment to an exposed environment. In new‐inactive Mpro a new cavity is present near the S2′ subsite, and the N‐terminal and C‐terminal tails, as well as the dimeric interface, are perturbed, with partial destabilization of the dimeric assembly. This novel conformation is relevant both for comprehension of the mechanism of action of Mpro within the catalytic cycle and for the successful structure‐based drug design of antiviral drugs. [ABSTRACT FROM AUTHOR]

Intelligent objects, autonomous factories and humans browsing the real world with artificial technology‐based capabilities is not the movie set of a new saga but what is going to happen with next‐generation electronics and bioelectronics fabricated with emerging materials, technologies, and devices. The emergence of (bio)electronics as a ubiquitous feature of an advanced modern society is posing the challenge of managing an ever‐increasing amount of e‐waste, also making the recovery more and more difficult. Thus, new design approaches are required considering that a possibly small but significant fraction of mass‐scale e‐products is inherently impossible to recover. In this perspective, organic materials and technologies can provide important solutions. This review presents and analyses green materials and technologies underpinning the development of sustainable organic transistors, which promise to become key components for Earth‐safe wide‐spread electronics and bioelectronics. [ABSTRACT FROM AUTHOR]

People's preferences for redistribution are a key component of redistributive policy design, yet how to elicit these preferences is still a matter of debate. We recruited a nationally representative sample of more than 5000 US respondents. We used an approach based on principles of justice to elicit people's preferences for redistribution across different domains. We compared people's preferences for the distribution of wealth, good educational resources, and good health status. We found that people have different preferences across domains: they accept higher inequality in wealth whereas they prefer more equal distributions in education and health. These preferences are consistent across different demographic groups. We discuss policymaking implications: when designing redistributive policies, policymakers should take this approach into account to trigger more favorable reactions to such policies. [ABSTRACT FROM AUTHOR]

Background: Single‐cell sequencing has been instrumental in understanding cell‐type specific changes in Alzheimer's disease (AD). While sequencing provides information about changes in individual cells, how these changes impact the interaction between cells is not as well‐defined. Understanding how the transcriptional and epigenetic changes that emerge during disease impact cellular communication will be critical in understanding key pathological changes that contribute to AD. Method: We performed single‐nucleus RNA and ATAC‐seq (10x Multiome) to investigate gene expression and epigenetic regulation of cells in the entorhinal cortex (ENT) of 2‐month and 8‐month‐old 5xFAD and WT mice (n = 2 for each age, condition), and used publicly available single‐nucleus RNA‐seq data from the ENT of patients with and without AD. We used CellChat and the new package NeuronChat to explore how intercellular communication networks change between healthy and AD humans and mice. Based on these results, we then explored relationships between chromatin accessibility and gene expression for genes of interest. Result: We observed changes in cell‐cell communication between AD and healthy samples in both mice and humans, particularly in the later stages of disease. The most prominent change was increased signaling from astrocytes to glutamatergic neurons in AD (Figure 1). This relationship included upregulation of neuroligin and ephrin‐A‐mediated signaling in AD, both previously implicated in synaptic regulation. In inter‐neuronal communications, the pathways most significantly disrupted in both human and mouse neurons were related to glutamatergic signaling. Multiple types of glutamate receptors were upregulated in both AD patients and 5xFAD mice in glutamatergic neurons, while GABAergic signaling did not appear to change. This finding is consistent with the hypothesis that glutamatergic neurons are hyperactive in AD and extends these observations by providing a potential mechanistic explanation of this phenomenon. Conclusion: Our results indicate that in patients with AD and 5xFAD mice, dysfunction of the glutamatergic system is a prominent feature of pathogenesis and includes both inter‐neuronal signaling and communication with astrocytes. These results provide a series of testable hypotheses to explore the consequences of the transcriptional and epigenetic changes on the circuit dysfunction observed in AD. [ABSTRACT FROM AUTHOR]

Anaphylaxis after mosquito bite is rare, but life threatening. No approved preventive therapy is available to date, but omalizumab could be a promising therapeutic option for reducing risk and improving quality of life in these patients. [ABSTRACT FROM AUTHOR]

The timely diagnosis of cystic pancreatic cancer precursors is of utmost importance to improve patients' low survival rate. Fine‐needle aspiration cytology is endowed with low diagnostic sensitivity, while more effective is the assay of markers, such as a mutated KRAS, in the cyst fluids. Next‐generation sequencing, detecting down to a single copy of a genomic marker, enables early diagnosis but the diagnostic sensitivity of high‐grade cysts, likely to become malignant, is low. Assaying both mutated KRAS and MUC1 protein markers can improve diagnostic accuracy. Their detection in blood would also be minimally invasive. Here, the mucinous lesions markers, KRAS and MUC1, are both successfully assayed in blood serum at the physical limit with the label‐free "Single‐Molecule assay with a large Transistor—SiMoT." This is a compelling proof of principle that the SiMoT platform holds high potential to enable a timely, minimally invasive, and accurate diagnosis of pancreatic cancer precursor cysts. [ABSTRACT FROM AUTHOR]

Background: Observational comparative effectiveness studies in allergen immunotherapy (AIT) represent an important evidence source answering research questions that can be challenging to obtain from randomized controlled trials (RCTs), such as long‐term benefits of AIT, the effects on asthma prevention and the onset of new allergen sensitizations. However, observational studies are prone to several sources of bias, which limit their reliability. The REal Life Evidence AssessmeNt Tool (RELEVANT) was recently developed to assist in quality appraisal of observational comparative research to enable identification of useful nonrandomized studies to be considered within guideline development. Objective: To systematically appraise the quality of published observational comparative AIT studies using RELEVANT. Methods: Observational studies comparing AIT to pharmacotherapy for respiratory allergies, assessing as outcome measures reduction of symptoms and/or medication use reduction, were retrieved by computerized bibliographic searches. According to RELEVANT, a failure to meet any one of primary items (background, design, measures, analysis, results, discussion/interpretation, and conflict of interest) represents a critical flaw, significantly undermining the validity of the study results. Results: The 14 studies identified supported the benefit of AIT in real‐life, which persists after treatment discontinuation. However, none of them met all the 7 primary RELEVANT criteria. The main defects were reported in the design (28.6% of studies), measures and analysis (64.3% of studies), and results (78.6% of studies) items, due to selection bias and lack of methods for adjusting controls. Half of the studies did not report on conflict of interest. Conclusion: There is a need for more robust observational research in AIT. RELEVANT appears as an easy‐to‐use and sensitive tool for quality appraisal in AIT studies. [ABSTRACT FROM AUTHOR]

We herein report the ammonium salt‐catalyzed synthesis of chiral 3,3‐disubstituted isoindolinones bearing a heteroatom functionality in the 3‐position. A broad variety of differently substituted CF3S‐ and RS‐derivatives were obtained with often high enantioselectivities when using Maruoka's bifunctional chiral ammonium salt catalyst. In addition, a first proof‐of‐concept for the racemic synthesis of the analogous F‐containing products was obtained as well, giving access to one of the rare examples of a fairly stable α‐F‐α‐amino acid derivative. [ABSTRACT FROM AUTHOR]

Side-dress N is a management strategy in maize (Zea Mays L.) production that can increase yield, reduce N leaching, and increase the probability that N remains post-flowering. This management adds cost, is time-sensitive, and can be difficult due to field shape and topography. A plantable, polymer-coated urea N bead of two sizes and two coating thicknesses was developed and field tested across multiple locations during 2015-2017 as a replacement to side-dress application. Locations differed in previous crop history and the initial N rates applied prior to treatments. Bead performance varied among locations but averaged 0.3 Mg ha-1 compared to an uncoated control or in-season urea-ammonium-nitrate (UAN) application. Bead application increased yield 0.8 Mg ha-1 when rainfall exceeded 225 mm between planting and R1 (silk appearance) but did not improve yield when rainfall was <125 mm. Nitrogen release from the bead was described by a thermal time function. A common exponential decay function was not adequate to describe the release of N across all locations indicating variation in release of N among locations driven by factors other than soil temperature. Slow-release, polymer-coated fertilizer, placed near the seed at planting, provides the option to apply supplemental N at planting, followed by N release later in the season, eliminating the need for in-season applications. Further research is needed to more closely match coating thickness and N release to crop N demand consistently across locations and development of equipment to enable one-pass seed planting and N application operations. [ABSTRACT FROM AUTHOR]

I Dear Editor i , Recently, dupilumab, an anti-IL-4R antibody, has become available for the treatment of moderate-to-severe atopic dermatitis (AD).1-4 Baseline patient characteristics that can be used as predictors of response to dupilumab treatment in AD patients have not yet been identified. In conclusion, this study highlights that specific baseline patient characteristics may help to predict treatment outcomes and the time of a complete response to dupilumab in AD. [Extracted from the article]

Conventionally fractionated chemoradiation (CRT) or chemotherapy (CHT) are considered as standard options in locally advanced pancreatic cancer (LAPC) while stereotactic body radiotherapy (SBRT) is an emerging treatment in this setting. The aim of this study was to compare two cohorts of LAPC patients treated with SBRT ± CHT vs CRT ± CHT in terms of local control (LC), distant metastases‐free survival (DMFS), progression‐free survival (PFS), overall survival (OS), and toxicity. Eighty patients were included. Patients in the two cohorts were matched according to: age ≤/>65 years, tumor diameter (two cut‐offs:

Purpose: To assess the feasibility of automated stereotactic volumetric modulated arc therapy (SBRT‐VMAT) planning using a simultaneous integrated boost (SIB) approach as a dose escalation strategy for SBRT in pancreatic cancer. Methods: Twelve patients with pancreatic cancer were retrospectively replanned. Dose prescription was 30 Gy to the planning target volume (PTV) and was escalated up to 50 Gy to the boost target volume (BTV) using a SIB technique in 5 fractions. All plans were generated by Pinnacle3 Autoplanning using 6MV dual‐arc VMAT technique for flattened (FF) and flattening filter‐free beams (FFF). An overlap volume (OLV) between the PRV duodenum and the PTV was defined to correlate with the ability to boost the BTV. Dosimetric metrics for BTV and PTV coverage, maximal doses for serial OARs, integral dose, conformation numbers, and dose contrast indexes were used to analyze the dosimetric results. Dose accuracy was validated using the PTW Octavius‐4D phantom together with the 1500 2D‐array. Differences between FF and FFF plans were quantified using the Wilcoxon matched‐pair signed rank. Results: Full prescription doses to the 95% of PTV and BTV can be delivered to patients with no OLV. BTV mean dose was >90% of the prescribed doses for all patients at all dose levels. Compared to FF plans, FFF plans showed significant reduced integral doses, larger number of MUs, and reduced beam‐on‐times up to 51% for the highest dose level. Despite plan complexity, pre‐treatment verification reported a gamma pass‐rate greater than the acceptance threshold of 95% for all FF and FFF plans for 3%‐2 mm criteria. Conclusions: The SIB‐SBRT strategy with Autoplanning was dosimetrically feasible. Ablative doses up to 50 Gy in 5 fractions can be delivered to the BTV for almost all patients respecting all the normal tissue constraints. A prospective clinical trial based on SBRT strategy using SIB‐VMAT technique with FFF beams seems to be justified. [ABSTRACT FROM AUTHOR]

Background: Dupilumab is an anti‐IL‐4Rα antibody used in the treatment of patients with moderate‐to‐severe atopic dermatitis (msAD). This study explored the potential benefit of dupilumab in perennial allergic rhinoconjunctivitis (PAR) and perennial allergic asthma (PAA) caused by indoor allergens in adults with msAD. Methods: This multicentric, prospective, observational, real‐life study included adult patients with msAD who had been treated with dupilumab in 16 Italian care centres. Efficacy outcomes regarding AD, PAR and PAA were collected at baseline and 16 weeks. Safety was also assessed. Results: We enrolled 123 patients with msAD. Between baseline and 16 weeks of treatment, the following measurements decreased statistically significantly: Eczema Area and Severity Index, SCOring AD, Patient‐Oriented Eczema Measure, pruritus score, sleep score, Dermatology Life Quality Index and IgE. Dupilumab treatment in patients with comorbid PAR (n = 41) was associated with significant improvements in PAR disease control (measured using a Rhinitis Control Scoring System) and in PAR Quality of life (QoL) (measured using the Rhinoconjunctivitis QoL Questionnaire scores). In 32 patients with comorbid PAA, dupilumab significantly improved PAA control (measured using the Asthma Control Test and five‐item Asthma Control Questionnaire scores) and disease‐related QoL (measured using the Asthma QoL Questionnaire scores). Thirty‐five patients (28.5%) developed conjunctivitis during the study period. Conclusion: These results support the benefits of dupilumab for adult patients with PAR and/or PAA associated with msAD. [ABSTRACT FROM AUTHOR]

Background: Major scientific societies, such as the EAACI or the AAAAI, do not express any suggestion on which form of allergen immunotherapy (AIT) is to be preferred (subcutaneous immunotherapy, SCIT, vs sublingual immunotherapy, SLIT). This choice could depend on their relative pharmacoeconomic value. Objective: To assess the cost‐effectiveness of AIT for grass pollen, administered as SCIT or SLIT. Methods: We created a Markovian Model, to evaluate, in a hypothetical cohort of adult patients suffering from moderate‐to‐severe rhino‐conjunctivitis with or without allergic asthma, the cost‐effectiveness of SLIT (tablets, Grazax® and Oralair®) or SCIT (various currently available products, plus indirect nonmedical costs, such as travel and productivity costs) in addition to pharmacological therapy, assuming a 9‐year horizon to capture AIT long‐term effects. The incremental cost‐effectiveness ratio (ICER) was calculated assuming pharmacological therapy as the reference comparator. Results: In the base case, SCIT was slightly more expensive, but more effective than SLIT, being the most cost‐effective option (ICER for SCIT, €11 418; ICER for SLIT, €15 212). ICERs greater than €120 000 for both SCIT and SLIT were demonstrated in a scenario assuming that low treatment persistence rates, which are common in real‐life, lead to absence of long‐term AIT clinical benefit. Considering indirect nonmedical costs SLIT resulted more cost‐effective than SCIT (ICER for SCIT, €17 318; ICER for SLIT, €15 212). Conclusion: In daily practice, AIT for grass pollens may be a cost‐effective option only in patients with low discontinuation rates. SCIT, which is less affected by this limitation than SLIT, seems the most cost‐effective AIT form. [ABSTRACT FROM AUTHOR]

Organic bioelectronic sensors are gaining momentum as they can combine high‐performance sensing level with flexible large‐area processable materials. This opens to potentially highly powerful sensing systems for point‐of‐care health monitoring and diagnostics at low cost. Prominent to detect biochemical recognition events, are electrolyte‐gated organic field‐effect transistors (EGOFETs) and organic electrochemical transistors (OECTs) as they are easily fabricated and operated. EGOFETs are recently shown to be capable of label‐free single‐molecule detections, even in serum. This progress report aims to provide a critical perspective through a selected overview of the literature on both EGOFET and OECT biosensors. Attention is paid to correctly attribute them to the potentiometric and amperometric biosensor categories, which is important to set the right conditions for quantification purposes. Moreover, to deepen the understanding of the sensing mechanisms, with the support of unpublished data, focus is put on two among the most critical aspects, namely, the capacitance interplay and the role of Faradaic currents. The final aim is to provide a rationale of the functional mechanisms encompassing both EGOFET and OECT sensors, to improve materials and devices' designs taking advantage of the processes that enhance the sensing response enabling the extremely high‐performance level resulting in ultimate sensitivity, selectivity, and fast response. [ABSTRACT FROM AUTHOR]

Herein we report the first asymmetric Michael reaction of arylidene‐isoxazol‐5‐one with 1,3‐diesters. Despite complex tautomer equilibria of the obtained Michael adducts, the one‐pot entrapping strategy by the aid of different electrophiles/protecting groups led to the selective isolation of diverse N‐substituted isoxazol‐5‐ones in very high overall yield and good enantioselectivity. Asymmetric three components Michael/electrophilic tautomer‐entrapping and four‐component Knoevenagel/Michael/electrophilic‐tautomer‐entrapping methodologies have also been developed. The enantiopurity of several final products was further increased after crystallization, up to > 99.9:0.1 er in good overall yields. [ABSTRACT FROM AUTHOR]

Summary: Hepatitis B virus (HBV) infection causes a self‐limiting disease in most individuals. However, < 10% of infected subjects develop a chronic disease. Genetic host variability of polymorphic genes at the interface of innate and acquired immunity, such as killer immunoglobulin‐like receptors (KIR), their human leucocyte antigen (HLA) and IgG allotypes (GM), could explain this different clinical picture. We previously showed a protective role of the KIR2DL3 gene for the development of chronic hepatitis B (CHB), and a detrimental role of the KIR ligand groups, HLA‐A‐Bw4 and HLA‐C2. We have expanded the previous analysis genotyping patients for GM23 and GM3/17 allotypes. The comparison of the patients with CHB with those who resolved HBV infection showed that the presence of GM17 allele virtually eliminated the risk of developing CHB (OR, 0·03; 95% CI, 0·004–0·16; P < 0·0001). In addition, the combination of GM17, KIR2DL3, HLA‐A‐Bw4 and HLA‐C2 was highly sensitive to predict the outcome of HBV infection. [ABSTRACT FROM AUTHOR]

Cardiac dysfunction is often observed in patients with cancer also representing a serious problem limiting chemotherapeutic intervention and even patient survival. In view of the recently established role of the immune system in the control of cancer growth, the present work has been undertaken to investigate the effects of a panel of the most important inflammatory cytokines on the integrity and function of mitochondria, as well as of the cytoskeleton, two key elements in the functioning of cardiomyocytes. Either mitochondria features or actomyosin cytoskeleton organization of in vitro‐cultured cardiomyocytes treated with different inflammatory cytokines were analyzed. In addition, to investigate the interplay between tumor growth and cardiac function in an in vivo system, immunocompetent female mice were inoculated with cancer cells and treated with the chemotherapeutic drug doxorubicin at a dosing schedule able to suppress tumor growth without inducing cardiac alterations. Analyses carried out in cardiomyocytes treated with the inflammatory cytokines, such as tumor necrosis factor α (TNF‐α), interferon γ (IFN‐γ), interleukin 6 (IL‐6), IL‐8, and IL‐1β revealed severe phenotypic changes, for example, of contractile cytoskeletal elements, mitochondrial membrane potential, mitochondrial reactive oxygen species production and mitochondria network organization. Accordingly, in immunocompetent mice, the tumor growth was accompanied by increased levels of the inflammatory cytokines TNF‐α, IFN‐γ, IL‐6, and IL‐8, either in serum or in the heart tissue, together with a significant reduction of ventricular systolic function. The alterations of mitochondria and of microfilament system of cardiomyocytes, due to the systemic inflammation associated with cancer growth, could be responsible for remote cardiac injury and impairment of systolic function observed in vivo. [ABSTRACT FROM AUTHOR]

Background: Large local reaction to Hymenoptera stings is usually defined as a swelling >10 cm which lasts longer than 24 hours, sometimes associated with erythema, pruritus and blisters. Currently, the risk of subsequent systemic reactions after re‐stings is considered low (2%‐15%). Therefore, a diagnostic workup in case of large local reaction is often judged unnecessary, as well as adrenaline auto‐injector and venom immunotherapy prescription. The aim of this study was to prospectively evaluate the outcome of re‐stings in a real‐world setting, in patients with a history of one previous large local reaction. Methods: We consecutively enrolled patients who experienced their first large local reaction (as per EAACI definition), treated with antihistamine and steroids. They were followed for field re‐stings and assessed for risk of subsequent systemic reactions. Results: We enrolled 662 patients. Out of the 225 re‐stung subjects, 24% did not experience reactions, 52% reported a second large local reaction and 24% had systemic reactions. The risk of subsequent systemic reactions was higher in case of skin test reactivity to Apis mellifera or Vespula species (OR 2.1 and 3.8, respectively), in particular if positive at 0.001 µg/mL concentration (OR 13.4 and 16.5, respectively). Conclusions: Systemic reactions, after a previous large local reaction, occur more frequently than that reported by literature. After analysing the predictive role of large local reactions for systemic reactions, we demonstrated that an accurate diagnostic workup may be considered, particularly skin tests. Further studies in different countries are needed to confirm these results and large local reaction management. [ABSTRACT FROM AUTHOR]

One of the major disease threats affecting the Mediterranean aquaculture industry is viral encephalopathy and retinopathy (VER). The target organs for Betanodavirus detection are the brain and eyes, obtained through lethal sampling. This study aimed to evaluate the efficacy and suitability of non‐lethal samples for detecting Betanodavirus in European seabass (Dicentrarchus labrax). European seabass juveniles were infected with Betanodavirus, by either an intramuscular injection or immersion (107TCID50/ml and 106TCID50/ml, respectively), and samples collected 7, 15 and 30 days post‐infection (dpi). The brain was collected as a lethal sample, and gills, caudal fin and blood as non‐lethal tissues for detecting Betanodavirus by quantitative reverse transcription PCR (RT‐qPCR). The presence of virus in non‐lethal tissues was inconsistent, with lower viral loads than in the brain. For blood, higher viral loads were detected in intramuscular‐infected fish at 15 dpi until the end of the challenge. Serum antibodies against Betanodavirus were assessed using an enzyme‐linked immunosorbent assay (ELISA). Antibodies were detected as early as 7 dpi, with higher mean antibody titres at 15 and 30 dpi. The presence of Betanodavirus‐specific antibodies indicates that this is a suitable evaluation method for detecting early stages of the infection. [ABSTRACT FROM AUTHOR]

The article discusses the epidemiological, clinical, and therapeutic qualities of patients with idiopathic nonhistaminergic acquired angioedema (InH-AAE) with prophylactic treatment of tranexamic acid (TXA) and omalizumab between 2005 and 2017. It states that InH-AAE is a rare cause of recurrent AE without wheals, and may be a mixture of angioedema subtypes, and that its diagnosis is exclusively clinical. Also noted is the potential of TXA and omalizumab for treatment.

Herein we report new methodologies for the synthesis of the challenging ketones 2‐cyanobenzophenones, based on Suzuki‐Miyaura type cross‐coupling reactions and very mild oxidation of 2‐benzylbenzonitriles. The investigation of the reactivity of the obtained ketones highlighted a very good electrophilicity in the presence of mild carbon‐ and hetero‐nucleophiles, allowing the synthesis of 3,3‐disubstituted isoindolin‐1‐ones. All the developed methodologies are highly efficient and tolerate combinations of functional groups present on both the aromatic rings. [ABSTRACT FROM AUTHOR]

We evaluated an EPID‐based in‐vivo dosimetry (IVD) method for the dose verification and the treatment reproducibility of lung SBRT‐VMAT treatments in clinical routine. Ten patients with lung metastases treated with Elekta VMAT technique were enrolled. All patients were irradiated in five consecutive fractions, with total doses of 50 Gy. Set‐up was carried out with the Elekta stereotactic body frame. Eight patients were simulated and treated using the Active Breath Control (ABC) system, a spirometer enabling patients to maintain a breath‐hold at a predetermined lung volume. Two patients were simulated and treated in free‐breathing using an abdominal compressor. IVD was performed using the SOFTDISO software. IVD tests were evaluated by means of (a) ratio R between daily in‐vivo isocenter dose and planned dose and (b) γ‐analysis between EPID integral portal images in terms of percentage of points with γ‐value smaller than one (γ%) and mean γ‐values (γmean) using a 3%(global)/3 mm criteria. Alert criteria of ±5% for R ratio, γ% < 90%, and γmean > 0.67 were chosen. 50 transit EPID images were acquired. For the patients treated with ABC spirometer, the results reported a high level of accuracy in dose delivery with 100% of tests within ±5%. The γ‐analysis showed a mean value of γmean equal to 0.21 (range: 0.04–0.56) and a mean γ% equal to 96.9 (range: 78–100). Relevant discrepancies were observed only for the two patients treated without ABC, mainly due to a blurring dose effect due to residual respiratory motion. Our method provided a fast and accurate procedure in clinical routine for verifying delivered dose as well as for detecting errors. [ABSTRACT FROM AUTHOR]

Key Clinical Message: We report the case of a patient with the coexistence of Graves' disease and autonomously functioning thyroid nodules. Because of the suspicious ultrasound pattern, he was submitted to fine‐needle aspiration of the hot nodule and cytology revealed a papillary thyroid cancer. After total thyroidectomy a papillary thyroid cancer was found. We report the case of a patient with the coexistence of Graves' disease and autonomously functioning thyroid nodules. Because of the suspicious ultrasound pattern, he was submitted to fine‐needle aspiration of the hot nodule and cytology revealed a papillary thyroid cancer. After total thyroidectomy a papillary thyroid cancer was found. [ABSTRACT FROM AUTHOR]

Background: Allergen immunotherapy (AIT) with mould extracts has been performed for many years but the final demonstration of its clinical efficacy is still missing, due to the small number of studies and their inconsistent results. Objective: To systematically review efficacy and safety of AIT for the treatment of respiratory allergies to moulds. Design: The primary outcomes were safety and reduction of symptoms (Symptom Score, SS) and medication use (Medication Score, MS) in patients treated with AIT compared to controls. The strength of the evidence was graded based on the risk of bias, consistency and magnitude of effect, according to the GRADE Working Group's guide. Data sources: Medline, Web of Science and the Cochrane Library (through September 2017) supplemented with manual searches of reference lists. Eligibility criteria: Randomized studies of intervention comparing AIT to placebo/pharmacotherapy. Studies not reporting on our outcome of interest or without a control population were excluded. Results: Nine studies (168 children, 99 adults; median sample size, 27) met the inclusion criteria. The risk of bias was moderate‐to‐high in all but one study. Low strength evidence supports the assumption that AIT is effective in reducing symptoms and medication use, with only four of nine studies reporting higher benefit of AIT vs. comparators. The highest benefit of AIT compared to pharmacotherapy/placebo was reported in studies with a longer follow‐up (SMD for MS from −3.96 to −3.97 in favour of AIT) and low risk of bias (VAS for SS: 66.3 ± 13 in AIT group; 186.6 ± 39 in comparators; P < 0.05). No difference was reported with respect to study sample size, route of administration, age of participants. Generalised adverse reactions were reported in 12.5% of participants treated with sublingual immunotherapy, and 37.2% of participants treated with subcutaneous immunotherapy. Conclusions: Low strength evidence suggests that mould AIT is efficacious for the treatment of respiratory allergies. High‐quality studies with an adequate sample size are needed. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to assess the feasibility to plan and deliver highly heterogeneous doses to symptomatic large tumors using volumetric modulated arc therapy (VMAT) and simultaneous integrated boost (SIB) during a short course palliative accelerated radiotherapy. Methods: A patient with a large symptomatic chordoma infiltrating the right gluteal region was selected. A modified SIB treatment was implemented to irradiate the central volume of the tumor (boost target volume, BTV) up to 10 Gy/fraction in a dose escalation trial while maintaining the remaining tumor volume (planning target volume, PTV) and the surrounding healthy tissues within 5 Gy/fraction in twice daily fractions for two consecutive days. Four SIB plans were generated in the dual‐arc modality; a basal dose of 20 Gy was prescribed to the PTV, while the BTV was boosted up to 40 Gy. For comparison purposes, plans obtained with a sequential boost (SEQ plans) were also generated. All plans were optimized to deliver at least 95% of the prescription dose to the targets. Dose contrast index (DCI), conformity index (CI), integral dose (ID), and the irradiated body volumes at 5, 10, and 20 Gy were evaluated. Results: At equal targets coverage, SIB plans provided major improvement in DCI, CI, and ID with respect to SEQ plans. When BTV dose escalated up to 200% of PTV prescription, DCI resulted in 66% for SIB plans and 37% for SEQ plans; the ID increase was only 11% for SIB plans (vs 27% for SEQ plans) and the increase in healthy tissues receiving more than 5, 10, and 20 Gy was less than 2%. Pretreatment dose verification reported a γ‐value passing rate greater than 95% with 3%(global)‐2 mm. Conclusion: A modified SIB technique is dosimetrically feasible for large tumors, where doses higher than the tolerance dose of healthy tissues are necessary to increase the therapeutic gain. [ABSTRACT FROM AUTHOR]

Summary: The main aim of this work was to evaluate the leaching of copper in grappa from distillation plant that treats Cabernet and Sangiovese marcs (Montepulciano and Chianti, Tuscany). Copper content (determined by atomic absorption spectrometry, AAS) was 1.05 ± 0.03 mg L−1 in industrial distillates (Cabernet marc, 82.3% alcohol, v/v), and 3.7 ± 0.2 μg L−1 in artificial grappa (62.0%, Cabernet) obtained by distilling marc in a laboratory‐scale glassware plant. The artificial grappa distillate was refluxed over copper shavings, and copper content, CCu, was analysed in relation to reflux time and wear of the copper bell. The results showed that CCu trend was almost linear with increasing alcohol concentration and constant reflux time, and vice versa. The ratios of selected volatile components were not influenced by reflux on the shavings. [ABSTRACT FROM AUTHOR]

Summary: Natural killer (NK) cells provide a major defence against human cytomegalovirus (HCMV) infection through the interaction of their surface receptors, including the activating and inhibitory killer immunoglobulin‐like receptors (KIRs), and human leucocyte antigen (HLA) class I molecules. Also γ marker (GM) allotypes, able to influence the NK antibody‐dependent cell‐mediated cytotoxicity, appear to be involved in the immunological control of virus infections, including HCMV. In some cases, their contribution requires epistatic interaction with other genes of the immune system, such as HLA. In the present report, with the aim of gaining insight into the immune mechanisms controlling HCMV, we have studied the possible associations among humoral and NK responses, and HCMV infections. In a previous study we assessed whether the KIR and HLA repertoire might influence the risk of developing symptomatic (n = 60) or asymptomatic (n = 60) disease after primary HCMV infection in the immunocompetent host. In the present study, the immunocompetent patients with primary symptomatic HCMV infection were genotyped for GM3/17 and GM23 allotypes, along with the 60 participants with a previous asymptomatic infection as controls. Notwithstanding the presence of missing data record, advanced missing data recovery techniques were able to show that individuals carrying the GM23 allotypes, both homozygous and heterozygous, GM17/17, HLA‐C2 and Bw4T KIR‐ligand groups are associated with the risk of developing symptomatic infection. Our findings on the role of both cellular and humoral immunity in the control of HCMV infection should be of value in guiding efforts to reduce HCMV‐associated health complications in the elderly, including immunosenescence, and in transplantation. [ABSTRACT FROM AUTHOR]