Plummer-Vinson syndrome (PVS) or Paterson-Brown-Kelly syndrome is a rare clinical condition characterized by the triad of esophageal webs/stenoses, iron-deficiency anemia, and progressively worsening dysphagia. It occurs mostly in Caucasian women in the fourth to seventh decades, particularly in northern countries. Esophageal webs and stenoses can be encountered during endoscopic evaluation for the patient’s complaint of dysphagia. Esophageal stenoses are characterized as simple or complex. A stenosis should be considered refractory once the patient has undergone several sequential dilatations within short intervals, optimized treatment for potential underlying causes (eosinophilic esophagitis or acid reflux), and after neuromuscular causes have been excluded. Glucocorticoid injection into a stenosis during an endoscopic dilation session has been proven to be beneficial as the initial treatment modality of refractory nonmalignant esophageal stenoses. We present a case of a 39-year-old woman with refractory esophageal stenosis in the setting of PVS which was successfully treated with serial endoscopic glucocorticoid injections while she received oral iron supplementation. To our knowledge, there are no previous cases of esophageal stenoses associated with PVS in the literature requiring endoscopic glucocorticoid injection for successful resolution. Plummer-Vinson syndrome (PVS) or Paterson-Brown-Kelly syndrome is a rare clinical condition characterized by the triad of esophageal webs/stenoses, iron-deficiency anemia, and progressively worsening dysphagia . When thA 39-year-old woman presented to our clinic complaining of weight loss of 3.2 kg associated with dysphagia for three months. Her past medical history was significant for hypothyroidism, chronic menorrhagia, and gastroesophageal reflux disease. She had a surgical history of laparoscopic cholecystectomy and a prior cesarean section. She reported progressively worsening dysphagia to solid foods and pills with chronic heavy menstrual periods. She was referred to a gynecologist due to chronic menorrhagia and was treated with intramuscular medroxyprogesterone acetate every 12 weeks which stopped the episodes of menorrhagia. Due to pill dysphagia, she was started on ferrous sulfate solution 220 mg orally twice daily and she remained adherent with iron supplementation throughout her entire clinical course. Her weight was 47.6 kg (baseline 55-60 kg). The complete blood count and iron panel were obtained before and one month after oral iron supplementation (Table A prior esophagogastroduodenoscopy (EGD) performed four years ago for dysphagia was normal. A repeat EGD was performed where she was found to have a benign-appearing 8 mm stenosis due to an upper esophageal web which was located 15 cm from the incisors  balloon dilator. Biopsies of normal-appearing esophageal mucosa in the upper and lower third of the esophagus were negative for eosinophilic esophagitis (EoE) showing 1-2 eosinophils per high-power field (15 or more eosinophils per high-power field is diagnostic of EoE). She had a total of three sessions of endoscopic dilation in two to three-week intervals without improvement of the stenosis beyond 10 mm. On her fourth EGD, the upper esophageal stenosis was dilated to 15 mm with a TTS balloon  during all esophageal dilations. With each endoscopic dilation, she reported improvement in her symptoms and eventually returned to a regular diet. Wireless pH monitoring over a 48-hour period (off of acid-suppressive medication for seven days) was done after the patient declined catheter-based pH monitoring and was negative for pathologic acid reflux . There was no gastrointestinal cause for anemia found on subsequent colonoscopy and small bowel video capsule endoscopy. Following medical therapy with iron supplementation and endoscopic therapy with triamcinolone and progressive TTS balloon dilations, she was found to have a weight of 64 kg (an increase of 20.9 kg from nadir).Esophageal stenosis should be considered refractory once a patient has undergone several sequential dilatations within short intervals, optimized treatment for potential underlying causes (eosinophilic esophagitis or acid reflux), and after neuromuscular causes have been excluded . NonmaliThere is a lower risk of stenosis recurrence and fewer sessions of serial endoscopic dilation associated with endoscopic glucocorticoid injection. A meta-analysis  involving 176 patients with refractory esophageal stenoses, glucocorticoid injection plus endoscopic dilation resulted in a lower risk of stenotic recurrence  = 0.51-0.81) and fewer endoscopic dilation sessions compared with dilation alone  [In the iron-deficient state in PVS, the gastrointestinal tract is susceptible and rapidly loses iron-dependent enzymes due to a high cell turnover, which leads to mucosal degeneration and web formation. Alternative proposed etiologies include genetic predisposition, malnutrition, and autoimmune processes . FollowiIt is unclear if the etiology of the stenosis influences the effect of steroid injection . The useOur success with regard to treating benign esophageal stenosis in our patient highlights the importance of considering endoscopic glucocorticoid injection as an initial treatment for refractory benign esophageal stenoses.To our knowledge, there have not been any previous cases of esophageal stenoses associated with PVS in the literature requiring endoscopic glucocorticoid injection for successful resolution. This case also shows the safety and feasibility of performing endoscopic triamcinolone injections for nonmalignant esophageal strictures, especially in the community-based hospital setting where access to metal, plastic, or biodegradable esophageal stents may be limited.


Endoscopic omental packing (EOP) is a technique used to close gastric perforations and is particularly useful for large defectsPerforation occurred during ESD for gastric cancer in the greater curvature of the lower body. Although conventional EOP was performed  and subVideo 1 Endoscopic omental packing in combination with the clip-and-snare method using pre-looping technique for gastric perforation.The patient’s subsequent clinical course was good and scarring of the post-ESD ulcer was confirmed .CSM-PLT represents a simple and reliable method for EOP. Previous reports demonstrated the effectiveness of EOP for gastric wall closure after endoscopic full-thickness resectionEndoscopy_UCTN_Code_CPL_1AH_2AZ


A 7-year-old girl with sickle cell trait was admitted with inability to bear weight and a painful rash. Examination demonstrated retiform purpura (RP) of the right leg Fig. A with teRP presents as branching purpuric patches and develops when dermal and subcutaneous blood vessels are compromised by vessel wall damage or lumen occlusion causing pain, necrosis, and ulceration . Underly


Teaching Point: High-pressure injection injuries are clinically significant injuries which may be underappreciated on initial physical exam and which require a high index of suspicion and early clinical intervention to avoid negative outcomes. A 46-year-old female presented to the ER with diffuse swelling of the left hand after attempting to fill a balloon from a helium tank. The patient’s distal thumb exhibited a punctate entry wound, pale tense skin, and absent capillary refill. Radiographs showed extensive diffuse subcutaneous emphysema consistent with helium insufflation  injury. High-pressure injection injuries are caused by high-pressure delivery devices such as paint guns or pressurized gas tanks . Injury


Magnetic resonance imaging (MRI) is the primary methodfor noninvasive investigations of the human brain in health, disease, anddevelopment but yields data that are difficult to interpret whenever themillimeter-scale voxels contain multiple microscopic tissue environmentswith different chemical and structural properties. We propose a novel MRIframework to quantify the microscopic heterogeneity of the living humanbrain as spatially resolved five-dimensional relaxation–diffusiondistributions by augmenting a conventional diffusion-weighted imagingsequence with signal encoding principles from multidimensional solid-statenuclear magnetic resonance (NMR) spectroscopy, relaxation–diffusioncorrelation methods from Laplace NMR of porous media, and Monte Carlo datainversion. The high dimensionality of the distribution space allowsresolution of multiple microscopic environments within each heterogeneousvoxel as well as their individual characterization with novel statisticalmeasures that combine the chemical sensitivity of the relaxation rates withthe link between microstructure and the anisotropic diffusivity of tissuewater. The proposed framework is demonstrated on a healthy volunteer usingboth exhaustive and clinically viable acquisition protocols. To measure and map thecellular architecture and molecular composition of the living human brain isa challenging experimental endeavor that promises far-reaching implicationsfor both clinical diagnosis and our understanding of normal brain function.Over recent decades, magnetic resonance imaging (MRI) methods have beencrucial for the progress of neuroanatomical studies .Most clinical MRI applications rely on detecting More detailed information can be obtained by taking into account that eachMRI voxel comprises hundreds of thousands of cells with potentiallydifferent properties, implying that the per-voxel signal may includecontributions from multiple microenvironments with distinct values of theMRI observables. To resolve the various microenvironments within a singlevoxel remains a highly challenging problem of vital importance for theprogression of quantitative MRI studies. The signals from heterogeneousmaterials are often approximated as integral transformations ofnonparametric distributions of relaxation rates or diffusivities, which may be estimated by Laplaceinversion of data acquired as a function of the relevant experimentalvariable . Within the context of humanbrain MRI, the components of the distributions have been assigned to waterpopulations residing in specific tissue microenvironments such as myelin and tumors . The powerto resolve and individually characterize the different components can beboosted by combining multiple relaxation- and diffusion-encoding blocks andanalyzing the data as joint probability distributions of the relevantobservables . These ideas follow the principlesof multidimensional nuclear magnetic resonance (NMR) spectroscopy and formthe basis for multidimensional Laplace NMR which has become routine in thefield of porous media  and is now being combined with MRI . Recently, similar relaxation–diffusioncorrelation protocols have been translated to in vivo studies using model-basedrather than nonparametric data inversion . So far, relaxation–diffusion correlation studieshave relied on the Stejskal–Tanner experiment , a pulsed gradient spin-echo (PGSE) sequence that has been inuse for more than 50 years and where the signal is encoded for diffusionalong a single axis using a pair of collinear gradient pulses. Thelimitations of the conventional experimental design become apparent whenconsidering a white matter voxel comprising anisotropic domains withmultiple orientations. When projected onto the measurement axis defined bythe magnetic field gradients, the combination of diffusion anisotropy andorientation dispersion gives rise to a broad distribution of effectivediffusivities  that is challenging toretrieve with nonparametric Laplace inversion and, most importantly,impossible to differentiate from a spread of isotropic diffusivities. Consequently, despite the fact that therelaxation–diffusion correlation yields more detailed information thanconventional quantitative MRI, the inherent limitations of theStejskal–Tanner experiment prevent unambiguous discrimination betweenisotropic and anisotropic contributions to the diffusivity distributions aswell as model-free resolution of tissue microenvironments for heterogeneousanisotropic materials such as brain tissue.We have recently shown that data acquisition and processing schemes forcorrelating isotropic and anisotropic nuclear interactions inmultidimensional solid-state NMR spectroscopy  can be translated to diffusion NMR , relaxation–diffusion correlation NMR, and diffusionMRI , yielding nonparametric diffusion tensordistributions  with resolution of multipleisotropic and anisotropic diffusion components. These “multidimensionaldiffusion MRI” methods  rely onvarying both the amplitude and orientation of the magnetic field gradientswithin a single encoding block in order to mimic the effects of samplereorientation  and rotor-synchronized radiofrequency pulse sequences  in multidimensional solid-stateNMR to target specific aspects of the tensorial property being investigated.Here, we incorporate these ideas into a clinically feasiblerelaxation–diffusion correlation MRI protocol to quantify the microscopicheterogeneity of the living human brain. The suggested acquisition andanalysis protocols resolve tissue heterogeneity on a five-dimensional spaceof transverse relaxation rates and axisymmetric diffusion tensors thatreport on the underlying chemical composition and microscopic geometry.Nonparametric relaxation–diffusion distributions are obtained for each voxelin the three-dimensional image using Monte Carlo data inversion to deal withthe nonuniqueness of the Laplace inversion and estimate the uncertainty ofquantitative parameters derived from the distributions. Subvoxel tissue environmentsare resolved without limiting assumptions on the number or properties of theindividual components and are characterized with statistical measures that haveintuitive relations with the local microstructure.22.1Figure 1a displays a pulse sequencewherein the signal Throughout the signal encoding process, the relaxation and diffusion ofwater are both affected by molecular exchange between chemically differentsites and interactions with cell membranes. Averaging all these complexeffects into sets of effective relaxation rates and apparent diffusiontensors, subvoxel composition can be reported as a collection ofindependent tissue microenvironments, each of which is characterized by aset of  was scanned on a Siemens MagnetomPrisma 3T system equipped with a 20-channel-receiver head coil, and capableof delivering gradients of 80 mT mhttps://github.com/jsjol/NOW,last access: 1 November 2019), including compensation for theeffects of concomitant gradients . This procedure yielded a pair of asymmetric gradient waveforms lasting30.8 and 25.0 ms, separated by approximately 8.0 ms. Linear encoding and gradient waveforms shown inFig. 1. The depicted waveforms give fourdistinct A total of 852 individual images were recorded at different combinations of have beenreviewed in both general  and magneticresonance  literature.While classical inversion methods can be successfully used to estimate the5D The procedure described above is performed voxel-wise, resulting in an arrayof spatially resolved Following the works of Prange and Song , we replace traditional regularization constraints with an unconstrained Monte Carlo approachthat estimates voxel-wise ensembles of https://github.com/JoaoPdAMartins/md-dmri(last access: 25 February 2020) .Inversion of the 45 min dataset took The nonparametric Monte Carlo inversion procedure was implemented in MATLABand is publicly available in our GitHub repository: 33.1The proposed acquisition protocol translates into distinctive signal decaycurves for each of the main components of the human brain. Indeed, voxelsencompassing either white matter (WM), gray matter (GM), or cerebrospinal fluid (CSF) are all characterized by clearly distinct signal patterns . The observeddifferences can be used to infer the gross Spatially resolved 5D Voxels containing pure GM or WM are characterized by clusters ofAs evidenced by Fig. 2c, pure GMvoxels yield bimodal distributions that feature a nearly symmetric spread ofcomponents around the 3.2The The three maps in the first column of Fig. 3 provide a rough spatial overview of the principal tissue types: The maps displayed in Fig. 3 can also beused to identify voxels containing WM3.3A more detailed picture of intra-voxel heterogeneity is obtained by dividingthe distribution space into smaller subspaces (“bins”). In line with earlydiffusion MRI works , we definethree bins that loosely capture the diffusion properties of theGlobal and bin-resolved averages for all the analyzed voxels of the entire3D image matrix are compiled in Fig. 5,where per-voxel average means of The minor differences between the relaxation rates of the thin and thickcomponents are also observed in the scatter plots ofFig. 5. A more detailed analysis showsthat distinct All bin-resolved The 3.4The acquisition protocol discussed thus far can be inserted without furtheralterations in research studies of brain disease, where subjects arerecruited for long scan sessions. However, the associated 45 min scan timeimpedes its use outside of a clinic-research setting. To assess thepotential for clinical translation of the proposed framework, we compare theperformance of the exhaustive 45 min protocol with that of an abbreviatedprotocol, compatible with the time frame of most clinical applications. Tothis end, we included two different 5D relaxation–diffusion MRI protocols ina single imaging session: the 45 min protocol described in the Methods section, andan abbreviated 15 min protocol whose details are contained in theSupplement. The two acquisition protocols were consecutively used withoutrepositioning the volunteer.The abbreviated dataset was inverted with the Monte Carlo algorithmdescribed above. The resulting 5D 4The proposed framework resolves intra-voxel heterogeneity on a 5D space oftransverse relaxation rates The protocol presented in this work shows promise for neuroanatomy studiesdealing with the resolution of specific microscopic features such as nervefiber-tracking through heterogeneous voxels  orfree water mapping . Within a clinicalsetting, disentangling different tissue signals is expected to be useful forpathological conditions associated with intra-voxel tissue heterogeneity,e.g. tumor infiltration in surrounding brain tissue, inflammation of cerebraltissue, or replacement of myelin with free water. In the latter example, theproposed echo times lead to an almost complete decay of the signalcontributions from myelin domains, meaning that the effects of axonaldemyelination would have to be probed indirectly by tracking a reduction ofthe signal fraction from anisotropic subvoxel components.Several approaches have been introduced in the diffusion MRI literaturewhere subvoxel composition is investigated by devising signal models withincreasingly complex priors and constraints . While such models can be used toinvestigate the conditions mentioned in the above paragraph, the attainedconclusions will be heavily dependent on the assumptions used to constructthe model . Hence, erroneousconclusions may be derived whenever the presupposed MR properties differfrom the underlying microstructure . Thislimitation is alleviated in the present framework where subvoxelheterogeneity is quantified with nonparametric distributions that areretrieved from the data with minimal assumptions on the underlying tissueproperties. Moreover, the vast majority of diffusion MRI models has been sofar implemented with conventional Stejskal–Tanner sequences, which are knownto convolve the signal contributions from Besides resolving the various microscopic domains within a voxel, we werealso capable of observing subtle differences in component-specificrelaxation rates. As mentioned before, this information is unattainable withclassical multi-echo At the cellular level, the translational motion of water inside the humanbrain is influenced by interactions with macromolecules and partiallypermeable membranes forming compartments with barrier spacings ranging fromnanometers for synaptic vesicles and myelin sheaths to micrometers for theplasma membranes of the axons. The diffusion of water during the 0.1 stimescale of MRI signal encoding is thus affected by a myriad of complexphenomena that are not explicitly accounted for in Eq. (2). Instead, we use the well-established approachof approximating the micrometer-scale water displacements as a distributionof anisotropic Gaussian contributions . Themeasured diffusivities may depend on the exact choice of experimentalvariables if the timing parameters of the gradient waveforms match thecharacteristic timescales of displacements between cellular barriers or molecular exchange between tissue environmentswith distinctly different diffusion properties . Byaugmenting our acquisition protocol with an experimental dimension in whichthe spectral profiles of the gradient waveforms are comprehensively varied, microscopic barrier spacings could in principle be estimated byexplicitly including the effects of restricted diffusion in the kernel ofEq. (2). Here we chose to minimize the influence oftime dependence by designing waveforms with similar gradient-modulationspectra.In the previous section, we mentioned that prolate . Recently, Veraart et al. (2017) estimated subtle differences in This work introduces and demonstrates a novel MRI framework, in which themicroscopic heterogeneity of the living human brain is characterized via 5Dcorrelations between the transverse relaxation rate 10.5194/mr-1-27-2020-supplementThe supplement related to this article is available online at: https://doi.org/10.5194/mr-1-27-2020-supplement.


Specialist palliative care (PC) is a limited resource, best conserved by identifying persons most likely to benefit from a PC consult. Little guidance is available for clinicians on whether/ when to consult PC. The authors previously developed empirically-derived consult criteria to guide burn providers in specialist PC consultation, refining them by expert panel input.A modified three-iteration Delphi process was employed to revise and develop consensus on empirically-derived PC consult criteria in burn patients. Eligible participants (N=202) were identified by (a) having published on burn and PC (b) presented nationally on burn and PC or (c) nomination by the study team as having equivalent expertise in the field.Forty-three individuals participated in Iteration 1; n=34 (79%) in Iteration 3, which rank-ordered three versions of criteria and invited further revisions. Consensus eliminated the most parsimonious version. Expert review panelists integrated feedback, yielding a consensus list with 6 criteria for PC consultation and 6 criteria for consideration of PC consult. Consult criteria include patient/family request; conflicted or unclear goals of care; and high modified Baux/SCORTEN scores. Criteria for consideration include no longer meeting milestones; assistance with symptom management; or cardiac arrest.Consensus among burn and PC providers enhances validity and supports clinical use to guide burn providers on patients most likely to benefit from specialist PC consultation. Future research should prospectively explore whether adherence to the criteria is associated with improved outcomes and potential further revision.Provides guidance on PC consultation and may be used to examine outcomes.


When removing large flat colonic polyps (LFCPs) en bloc endoscopic submucosal dissection (ESD) may be suitable; however, it requires significant expertise and a long procedural time. The use of a conventional monopolar snare for endoscopic mucosal resection (EMR) of large lesions increases the risk of deep mural injuryThe Dragonare dedicated bipolar soft snare  has a unique mechanism where one electrode is at the tip of the snare and the other at the sheath, which allows uniform cauterization of the tissue. The soft nature of the snare allows stabilization of its tip at the distal margin of the lesion while opening the snare, thereby enabling en bloc resection of LFCPs. This requires a slower cutting technique compared with monopolar devices. Herein, we report two cases in which EMR was performed using the bipolar soft snare (26 mm) for LFCPs .Video 1 Two cases in which endoscopic mucosal resection is performed using a dedicated bipolar soft snare (26 mm) for large flat colonic polyps.The first patient was a 78-year-old man who had a 25-mm nongranular laterally spreading tumor (LST) found in his descending colon . AlthouThe second patient was an 86-year-old man who had a 30-mm granular-type LST found in his ascending colon . InjectBEMR with dedicated snares could be a new alternative when treating LFCPs. ESD can be replaced with BEMR for eligible polyps.Endoscopy_UCTN_Code_TTT_1AQ_2AD


A 25-year-old man with recently diagnosed acquired immunodeficiency syndrome (AIDS) was referred for consultation because of multiple intraoral lesions that had developed within past 2 months. Physical examination revealed diffuse multinodular purplish-red lesions with spontaneous bleeding affecting both the maxillary and mandibular gingiva . Histopa,KS is a multifocal angioproliferative disorder associated with HHV-8All procedures involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.


Magnetic resonance imaging-guided prostate biopsies have revolutionized the detection of clinically significant prostate cancer (csPCa) within the last decade . Using aThe authors of the study presented here have done a well thought out analysis to determine the distance between systematic cores containing csPCa and the ROI in 505 consecutive patients undergoing TB plus SB . This prIn 2019, the PIRADS-committee recommend TB of the ROI and a 5-mm penumbra for PIRADS 4 and 5 lesions . MoreoveIn conclusion, this study significantly contributes to the understanding of perilesional sampling in men undergoing prostate biopsy. However, confirmatory studies are needed to show if a risk-group based approach by PIRADS-score and PSA density has the potential to set up TB plus perilesional sampling biopsies as a new standard.


However, in case of preoperatively confirmed lymph node metastasis to the neck, patients are generally precluded surgery. The concurrent palliative treatment approach is associated with a limited 1 year survival of 32–39%. An alternative treatment approach would be neoadjuvant chemoradiotherapy followed by robot-assisted minimally invasive esophagectomy (RAMIE) with three-field lymphadenectomy, including the cervical lymph nodes. Whether this would be feasible and safe for the Western population was unclear up to now.Esophageal cancer remains a devastating disease, of which the incidence is increasing.2 Moreover, postoperative complications are comparable to those reported after curative treatment by high-volume centers and randomized trials. Overall 1 year survival was higher (85%) than reported for palliative treatment approaches, though this was not a primary endpoint for this study. An important finding was the high rate of interval metastasis in patients presenting with concomitant celiac trunk lymph node metastasis as well as poorly differentiated tumors. Additionally, patients rarely had cervical lymph node metastasis contralateral to the preoperatively detected cervical lymph node metastasis.This study shows that robot-assisted minimally invasive esophagectomy (RAMIE) with three-field lymphadenectomy is feasible in patients with resectable esophageal cancer presenting with cervical lymph node metastasis in a Western population.3 followed by restaging before entering the NODE treatment. The other patients will receive upfront the NODE protocol as described here. A bilateral cervical lymph node has been found unnecessary and will be replaced by a unilateral dissection. This study will compare the survival of patients who receive this treatment protocol with palliatively treated patients in the population.The results of this study will be used to design a nationwide multicenter study. In this prospective cohort trial, patients with celiac trunk metastasis or poorly differentiated tumors will first receive a potent systemic therapy [fluorouracil + leucovorin + oxaliplatin + docetaxel (FLOT) combined with trastuzumab for Her2-Neu-positive tumors] combined with immunotherapye


Medicare Part D prescription drug plans must offer medication therapy management (MTM) services to qualified enrollees. Eligibility criteria used by plan sponsors are restrictive, and fewer than 10% of Part D enrollees receive MTM services. The extent to which plan criteria identify beneficiaries most at risk for suboptimal medication use is unknown.To (a) evaluate potential underuse of and poor adherence to evidence-based medications used in the treatment of Medicare beneficiaries with diabetes, heart failure, and chronic obstructive pulmonary disease (COPD) over 3 years; (b) determine whether MTM eligibility criteria used by the modal Part D plan in 2011  identified Part D enrollees at greatest risk for underuse of and poor adherence to these drugs; and (c) demonstrate how sensitive MTM eligibility is to variations in criteria levels.Study subjects were selected from a 5% random sample of Part D enrollees with 1 or more of these diseases in 2006 and followed through 2008 or death. Longitudinal patterns of exposure and adherence to angiotensin-converting-enzyme inhibitor/angiotensin receptor blockers, beta-blockers, and COPD controller drugs were tracked comparing patterns for enrollees meeting/not meeting the modal 2011 MTM eligibility criteria.Use of evidence-based medication was consistently suboptimal for every disease cohort studied. Higher rates of exposure and adherence were observed among those with high drug spending taking multiple Part D drugs. Current MTM criteria were found to target beneficiaries with above average utilization of evidence-based medication and to exclude those with more problematic utilization patterns. We estimate that lowering the maximum required drug count from 8 to 2 would increase the percentage of beneficiaries eligible for MTM by two thirds.Our findings suggest that MTM eligibility criteria are not optimally targeted to capture underuse of and poor adherence to evidence-based medications. Policymakers should weigh the pros and cons of loosening restrictive MTM eligibility criteria to target patients with potentially greater needs.


E. coli MutT protein, that degrades 8-oxodGTP to prevent the incorporation of potentially miscoding 8-oxodG during DNA replication [E. coli, MutT counteracts spontaneous mutagenesis and mutT mutants have one of the highest known spontaneous mutation rates. Consistent with a similarly powerful antimutagenic role, enhanced nucleotide pool editing in human or mouse cells overexpressing hMTH1 significantly reduces the extremely high spontaneous mutation rates that result from a defect in DNA mismatch repair [in vivo overexpression of hMTH1 in transgenic C57BL/6J mice (hMTH1-Tg mice) protects them against age-related increases in micronucleus frequency [The universality and inevitability of the aging process suggests that the underlying mechanisms are likely to be similar across animal species and that data from animal models can therefore potentially inform human aging. Recent experiments using an engineered mouse strain indicate a plausible role for the early acquisition of oxygen-related mutations in the aging process. Altered mitochondrial function and increased steady-state levels of reactive oxygen species (ROS) feature in several models of cellular senescence and aging. In general, cellular macromolecules  are regarded as the targets for damage by ROS. The nucleotide pool that provides DNA replication precursors is also a significant ROS target and oxidation damage to deoxynucleoside triphosphates is now implicated in influencing longevity. The major product of oxidation in the nucleotide pool – 8-oxo-7,8-dihydrodeoxyguanosine triphosphate (8-oxodGTP) – is mutagenic. Human cells encode a nucleotide hydrolase hMTH1), the homolog of the , the homh repair . hMTH1 ah repair  and its h repair . In addirequency .hMTH1 overexpression in young hMTH1-Tg mice has a surprising impact on their general metabolism - including mitochondrial metabolism and the TCA cycle . At two The protective effect of hMTH1 overexpression is confined to young mice and the behaviour of adult (7-month-old) animals is strikingly different. By this age WT mice maintained on a normal laboratory diet appear free of stress related to nucleotide precursor oxidation and hMTH1 overexpression in the hMTH1-Tg mice has no detectable effect on their liver metabolome. Furthermore, a 5-week HFD challenge to these adult mice elicits little in the way of metabolic changes or other oxidative stress markers. The responses of adult WT and hMTH1-Tg mice are closely similar and the protective effect of hMTH1 overexpression is redundant in these adult mice.The canonical nucleotide hydrolase activity of hMTH1 is antimutagenic. Since the effects of its overexpression appear to be largely confined to young mice, it seems likely that this is related to the developmental pattern of these mice. The birth weights, subsequent growth rates and adult bodyweights of WT and hMTH1-Tg mice are indistinguishable. In both genotypes, growth is extremely rapid between conception and around 10 weeks after birth during which time the animals attain more than 80% of their final body mass . In WT min vitro models [The involvement of mutagenesis in aging is not straightforward. Aging affects everyone. By analogy, although only approximately one in three people will be diagnosed with cancer – a mutation-driven pathology - all three individuals will inevitably succumb to aging. Clearly the cancer paradigm of selection of key ‘driver’ mutations is unlikely to apply to aging. An alternative possibility is that all mutated genes are potential contributors to aging. They might do this via detrimental effects on the proteome that worsen with time. The altered primary sequence of a protein expressed from a mutated gene increases its risk of misfolding and misfolded proteins are highly susceptible to oxidation and aggregation. The powerful impairment of cellular systems by misfolded and oxidized proteins has been extensively documented in o models . Proteino models . On thisThe enhanced longevity of hMTH1-Tg mice is consistent with the prevention of early-life ROS-related mutations via nucleotide pool cleansing. It remains to be experimentally determined whether a reduced mutational burden extends their healthy lifespan by slowing the time-dependent accumulation of toxic misfolded and oxidized protein aggregates.


Leiomyomas are benign smooth muscle tumors, and retroperitoneal leiomyomas without coexisting uterine leiomyomas are extremely rare. Mitotically active leiomyomas, which are leiomyomas with increased mitotic activity, are rarely observed in postmenopausal women, except under the influence of exogenous hormones. This report presents a rare case of a retroperitoneal mitotically active leiomyoma in a postmenopausal woman. The patient presented with an abdominal mass and underwent surgical resection of the retroperitoneal tumor. Pathological examination revealed a mitotically active retroperitoneal leiomyoma with 31 mitotic figures per 10 high-power fields. The patient did not experience recurrence during the 2-year follow-up period. This case highlights the need to consider retroperitoneal mitotically active leiomyomas in postmenopausal women and suggests that myomectomy can prevent their recurrence. Leiomyomas are benign smooth muscle tumors that represent the most common gynecological neoplasms ; howeverAn 82-year-old woman with an abdominal mass was referred to our hospital. She had previously undergone ovarian mucinous cystadenoma with bilateral salpingo-oophorectomy 3 years prior, and had uterine leiomyoma. Abdominal contrast-enhanced computed tomography revealed a well-defined heterogeneously enhanced mass near the left ovarian artery and ureter . No signDuring surgery, we observed a retroperitoneal tumor with a smooth surface at the back of the sigmoid mesentery . The tumPathological reports revealed a smooth muscle tumor with 31 mitotic figures per 10 high-power fields, but lacking cytologic atypia and tumor cell necrosis . Based oThe patient was doing well at the outpatient follow-up at 2 years, with no recurrence.The lessons learned from this case are as follows: (i) retroperitoneal mitotically active leiomyomas can occur in postmenopausal women and (ii) myomectomy does not result in tumor recurrence.Retroperitoneal mitotically active leiomyomas can be observed in postmenopausal women. Leiomyomas are non-cancerous monoclonal tumors that arise from smooth muscle cells and fibroblasts that can exhibit various types of smooth muscle differentiation. Although various atypical localizations of leiomyomas have been reported, growth in the retroperitoneum is extremely rare . AdditioEven after myomectomy of the retroperitoneal mitotically active leiomyoma, no recurrence or metastasis was observed during follow-up. In general, classic leiomyomas have the following features: mitotic index of <5 mitotic figures per 10 high-power fields, mild cytologic atypia and no tumor cell necrosis, whereas a diagnosis of leiomyosarcoma requires at least two of the following three features; mitotic index of ≥10 mitotic figures per 10 high-power fields, moderate to severe cytologic atypia or presence of tumor cell necrosis . SeveralIn conclusion, this case report indicated that mitotically active leiomyomas can occur after menopause and are curable by myomectomy without the need for postoperative chemotherapy or pelvic radiotherapy. Further studies are required to determine the optimal treatment for mitotically active retroperitoneal leiomyomas.


The COVID-19 pandemic prompted healthcare organizations around the country to rapidly set up infusion centers that were solely dedicated to delivering outpatient COVID-19 monoclonal (mAb) and antiviral infusions. We capture the process of setting up these mAb infusion centers from the perspectives of key stakeholders. These lessons learnt may inform or refine actions in future pandemics.A realist interview approach was undertaken to evaluate the effectiveness of the program development with ten key stakeholders and healthcare workers who were involved. In contrast to traditional interviewing methods where a straight question leads to a straight answer, realist interviewing involves capturing the interviewees’ experiences through conversations of teaching and learning. We interviewed ten key stakeholders and healthcare workers who were involved with developing the mAb infusion process from Dec 13th, 2021, to Jan 19th, 2022, over online videoconferencing.A causal mechanism diagram using a context-mechanism outcome configuration was identified. There was a rapid development of multiple infusion sites over a short time frame with dynamic staffing and patient appointment models leading to rapid increases in mAb infusion capacity in southwestern Virginia.Figure 1.Causal mechanism diagram using a CMO configuration for the successful attributes leading to eligible patients treated with monoclonal antibodies.Strong clinical leadership, a robust communication and feedback framework and shared goals were identified by stakeholders as pivotal in the success of a COVID-19 monoclonal antibody infusion program for a health care system. Pandemic preparedness strategies should hardwire and leverage these features for resiliency.All Authors: No reported disclosures


These signs are the characteristic of fibroblast growth factor 23 (FGF23)-related hypophosphatemic osteomalacia, and the serum FGF23 levels were high . Although she was suspected to have tumor-induced osteomalacia, systemic venous samplings of FGF23 and 111In-octreotide somatostatin receptor scintigraphy were unable to identify the tumor. Her symptoms and multiple uptake on bone scintigraphy almost disappeared after initiating active vitamin D and phosphate replacement , (2)lacement . AlthougNone Naoya Fujita wrote the first draft. Yosuke Ono suggested improvements and revised the manuscript.Written informed consent was obtained from the patient to publish this report in accordance with the journal’s patient consent policy.


An ectopic pregnancy occurs when an embryo implants outside of the uterus, usually in a fallopian tube. When detected early, treatment is often with a medication called methotrexate. When methotrexate does not work, surgery is required. A recent clinical trial of ectopic pregnancy treatment  found that adding a drug called gefitinib to methotrexate did not reduce the need for surgery. We have used data from the GEM3 trial, combined with data collected 12 months after the trial finished, to investigate post-methotrexate pregnancy outcomes. We found no difference in pregnancy rates, pregnancy loss rates and recurrent ectopic pregnancy rates between those treated medically only and those who subsequently also needed surgery. The surgical technique used also did not affect pregnancy rates. This research provides reassurance that women with ectopic pregnancies treated medically who need surgery have similar post-treatment pregnancy outcomes to those treated successfully medically. Pre-treatment counselling for women with unruptured tubal ectopic pregnancies considering their treatment options requires the provision of information on post-treatment pregnancy outcomes, including rates of ectopic pregnancy recurrence. Current UK NICE early pregnancy guidelines are based on low-quality evidence and estimate the long-term ectopic pregnancy recurrence rate at ~18.5% . FurtherWe describe subsequent pregnancy outcomes in women with tubal ectopic pregnancy managed with methotrexate using data from a UK multicentre randomised controlled trial comparing methotrexate and gefitinib vs methotrexate and placebo for the treatment of tubal ectopic pregnancy . Follow-up data from both randomisation groups  were combined owing to no between-group differences in subsequent pregnancy outcomes .This project was supported by funding from the This study is a follow-up analysis of participants from the GEM3 trial (ISRCTN Registry ISRCTN67795930).SCM drafted the manuscript. CAM analysed the data. All authors reviewed and contributed to the final manuscript.


A 74-year-old male was admitted to the emergency department with cutaneous lesions on his face resembling raccoon eyes and lesions on his neck and shoulders . He had Primary amyloidosis involves the extracellular deposition of amyloid protein in various tissues, causing multiorgan damage . Raccoon


Intraoperative aortic valve evaluation should be accurate in valve-sparing root replacement to minimize postoperative aortic valve regurgitation. Ascending aorta de-clamping and weaning of cardiopulmonary bypass are required in intraoperative transoesophageal echocardiography. Aortic valve endoscopy aids in the magnification of structures and enables image sharing within the operative team. While a rigid endoscope and saline infusion line are directly inserted from the Valsalva graft end, a Kelly clamp is needed for graft gap closure, affecting the valve morphology due to graft deformation. The accurate inner pressure of the neo-Valsalva sinus cannot be measured in this method. We propose a technique to accurately evaluate aortic valve conformation using a balloon blunt-tip system that enables aortic valve evaluation under the measured pressure and without Valsalva graft deformation. Valve-sparing root replacement is advantageous over the Bentall technique and provides excellent long-term results [1]. Valve-sparing root replacement is advantageous over the Bentall technique and provides excellent long-term results . IntraopIn conventional endoscopic evaluation, the endoscope and saline infusion line are directly inserted from the Valsalva graft end, and Kelly clamps are used for gap closure. However, observing the natural aortic valve morphology is difficult because NVS is deformed by clamping and endoscope operation Fig. A. FurtheThe Kii balloon blunt-tip (BBT) system  is a camera port used for laparoscopic surgery Fig. B. With aA 60-year-old man, diagnosed with non-communicating DeBakey type-II aortic dissection, was referred to our hospital. A dilated aortic root and ascending aorta with tears were observed on four-dimensional computed tomography angiography. Echocardiography revealed mild-to-moderate AR. After performing median sternotomy and establishing cardiopulmonary bypass, an aortic cross-clamp was placed near the innominate trunk to induce cardiac arrest. The aortic annulus diameter and non-coronary cusp-left coronary cusp commissure height were 26 and 24 mm, respectively. A 26-mm Gelweave™ Valsalva graft  was selected.After partial aortic arch replacement, the root reconstruction was resumed. After placing the Valsalva graft, we evaluated the aortic valve using the BBT system. The NVS was marked to orient the valvular cusps. The balloon and softgel cone were positioned to facilitate closure; the inner BBT cylinder was removed before insertion into the graft. The balloon was gently inflated to fix the BBT on the graft tubing and to close the NVS; a rigid endoscope was inserted.Saline infusion and manometric lines were connected to stopcock of the BBT system. Saline was infused into the NVS to achieve a 70-mmHg pressure Fig. A. The aoIntraoperative transoesophageal and postoperative transthoracic echocardiography revealed no residual AR.The BBT system is universally used in laparoscopic surgery. Balloon size can be regulated according to the graft diameter and the graft can be sufficiently closed. Using the balloon and softgel cone together, the distal end is closed without deformation. The system’s stopcock facilitates saline infusion into NVS and simultaneously measures inner pressure. This technique allows us to evaluate the morphology of aortic valve not only without graft deforming but also under artificial diastolic pressure. That provided the opportunity to correct cusp prolapse or commissure fixed position and might improve the quality and increase the reproducibility of valve repair.To avoid mechanical injury to the aortic valve, the graft’s tube portion should be maintained above the commissure fixation point Fig. C and 25 The BBT system facilitates simple and accurate physiological evaluation of valve-sparing root replacement.


A 12-year-old Caucasian male presented to the clinic with a displaced, segmental left clavicle fracture involving the distal clavicle after falling from a zip line. He was treated non-operatively in a sling and returned to normal activities without restrictions after three months. At one year, the patient was able to maintain his pre-injury baseline function without limitations of his left shoulder. While no clear guidelines for operative treatment of segmental clavicle fractures in the adolescent population exist in the current literature, this report illustrates an excellent patient outcome following conservative therapy of a segmental clavicle fracture involving the middle one-third and distal clavicle in a young adolescent with open physis. Clavicle fractures are common pediatric injuries in which the majority are treated non-operatively . The annA 12-year-old Caucasian male with no significant past medical history presented to the clinic with a closed left clavicle fracture after falling from a zip line 12 days prior. A physical exam showed a deformity over the left clavicle without appreciable skin tenting or neurovascular injury. Initial radiographs were obtained demonstrating a displaced, segmental clavicle fracture involving the middle one-third and distal clavicle, lateral to the coracoid  with mid-diaphyseal clavicle fracture malunions after non-operative treatment. All patients in the given study presented with an initial fracture displacement greater than 2 centimeters and were followed for two years. The authors concluded that radiographic malunion in adolescents does not result in clinically meaningful loss of shoulder motion or strength . A retro.2 years Although non-operative management has traditionally been the treatment of choice for pediatric clavicle fractures, there has been a recent increase in operative management. As patients enter adolescence they become more active than adults, gradually lose their remodeling potential, and may experience greater functional impairment from residual disability. The initial displacement of a clavicle fracture is an important factor in treatment decision. Initial fracture shortening of >20mm is associated with nonunion and unsatisfactory results . A CanadA disparity exists amongst surgeons regarding the treatment of adolescent clavicle fractures as shown by a survey of 302 members of the Pediatric Orthopaedic Society of North America (POSNA). Surgeons were nearly unanimously in favor of non-operative treatment in younger patients. However, regarding isolated segmental clavicle fractures, treatment preferences were split between operative and non-operative management with surgeons more likely to operate on adolescents age 16-19 years than age 12-15 years. Additionally, surgeons with less than five years of experience were more likely to choose operative treatment .Clavicle fractures in the adolescent population have no clear consensus on treatment, particularly when considering the 12-15-year-old age group. Currently, no literature supports the age range at which surgeons should adopt more aggressive treatment options related to fracture characteristics. This report demonstrates that a segmental clavicle fracture involving the middle one-third and distal clavicle in a young adolescent with open physes may be managed conservatively with good outcomes.


Intraductal papillary neoplasm of the bile duct (IPNB) is a type of epithelial tumor characterized by papillary proliferation within the bile duct. It is defined histologically as a papillary or villous neoplasm covering the delicate fibrovascular stalks within the bile ductsThe patient was a 79-year-old man referred to our hospital for detailed examination of intrahepatic bile duct dilatation. Marked dilatation of the left intrahepatic bile duct and a suspected intrahepatic bile duct tumor were observed on contrast-enhanced computed tomography and magnetic resonance cholangiopancreatography . EUS coVideo 1 Detective flow imaging (DFI), a novel imaging technique for low velocity blood flow, is used to identify the fibrovascular stems in intraductal papillary neoplasm of the bile duct (IPNB) that could not be detected by conventional imaging modalities.To our knowledge, this is the first report on the use of DFI to detect dendritic vessels within an intrahepatic bile duct tumor. DFI, which can capture tumor hemodynamics not detectable by conventional blood flow imaging, may be useful in differentiating intrahepatic bile duct tumors, including IPNB.Endoscopy_UCTN_Code_TTT_1AS_2AD


Molecular genetic testing confirmed a de novo heterozygous pathogenic variant in TCS2. The patient was commenced on everolimus and has had no complications.A 32-year-old man with a known diagnosis of tuberous sclerosis presented with early satiety and abdominal discomfort. Investigations revealed multiple large angiomyolipoma arising from and surrounding both kidneys. Axial and coronal true fast imaging with steady state precession magnetic resonance imaging (MRI) scans  showed tAngiomyolipomas are a common feature of tuberous sclerosis, occurring in 60–80% of patients  and are


Physical education is an important context to contribute students’ physical activity in childhood and adolescence. However, negative physical education experiences may have a long-lasting association on students’ willingness to participate in physical activity. The associations between students’ anxiety in physical education and physical fitness have not been previously investigated. The aim of this longitudinal study was to analyse associations between physical education anxiety and physical fitness through five years.Participants of this study included 1147 Grade 5 students  (mean age: 11.27(0.32) years) at the baseline measure. These participants were measured annually between Grades 5 to 9. The Finnish version of the Physical Education State Anxiety Scale  was used to measure cognitive anxiety in physical education. Physical fitness was measured by 20meters shuttle run test (cardiorespiratory fitness) and curl-up and push-up tests (muscular fitness). Sex, BMI and peak height velocity was used as covariates in the analysis. Associations between study variables were measured by the Random Intercept Cross-Lagged Panel Model using Mplus statistical software.Between level results (squared multiple correlations) of the analysis demonstrated that cognitive anxiety was related to cardiorespiratory (-.32) and muscular fitness (-.34) over five years. Additionally, sex , BMI (.16) and peak high velocity (-.23) had significant associations with cognitive anxiety.This study revealed that cognitive anxiety in physical education has an influence on student’s physical fitness longitudinally. These findings were similar between anxiety and cardiorespiratory fitness and between anxiety and muscular fitness. Results demonstrate that negative physical education experiences have an association on cardiorespiratory and muscular fitness from late childhood to adolescence. Constructs of the Self-determination theory  and Achievement goals theory (task orientation) are helpful when implementing positive pedagogy in physical education.Finnish Ministry of Education and culture funded this study.


Allergic Rhinitis is a common Ear, Nose and Throat disorder. Asthma and Allergic Rhinitis are diseases with similar underlying mechanism and pathogenesis. The aim of this survey was to highlight current treatment trends for Allergic Rhinitis and Asthma.A questionnaire was emailed to all registered consultant members of the British Association of Otorhinolaryngologists - Head and Neck Surgeons regarding the management of patients with Allergic Rhinitis and related disorders.Survey response rate was 56%. The results indicate a various approach in the investigation and management of Allergic Rhinitis compatible with recommendations from the Allergic Rhinitis and Its Impact on Asthma guidelines in collaboration with the World Health Organisation.A combined management approach for patients with Allergic Rhinitis and concomitant Asthma may reduce medical treatment costs for these conditions and improve symptom control and quality of life. The definition of Allergic Rhinitis (AR) was formulated by Hansel in 1929 [The nasal passage and paranasal sinuses are an integral part of the respiratory tract and patients may have rhinitis without sinusitis, but not sinusitis without rhinitis, hence the term rhinitis has been replaced in modern ENT literature by the more accurate term rhinosinusitis . AR and The aetiology of AR is multi-factorial and the diagnostic and therapeutic choices remain diverse. The aim of this questionnaire survey was to highlight the treatment trends in the management of AR amongst UK-based otolaryngologists.A questionnaire (Appendix 1) was emailed via ENT UK to the email addresses of all registered consultant members of the British Association of Otorhinolaryngologists - Head and Neck Surgeons (BAO-HNS). Survey recipients were asked 1) about their familiarity with the Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines in collaboration with the World Health Organisation (WHO), 2) about the type of investigations, treatment regimes and follow-up arrangements for AR patients and 3) about whether they give to patients advice leaflets on life style changes including education and allergen avoidance. All participants had the opportunity to answer anonymously.A total of 551 questionnaires were emailed. There were 309 replies (56% response rate). All consultants were familiar with the association between AR and Asthma but only 63% of the respondents were familiar with the ARIA guidelines. Seventy seven (25%) of otolaryngologists managed AR patients of which a 20 - 30% proportion had associated symptoms or a diagnosis of Asthma . Only nine consultants (3%) arranged pulmonary spirometry Figure .Fifty six per cent of otolaryngologists preferred the management pathway of starting treatment and then discharging AR patients to General Practitioners (GPs) for further follow-up. However three (1%) consultants managed and subsequently referred AR patients to a respiratory physician Figure .In total two hundred and forty (78%) of otolaryngologists provided patient leaflets on life-style changes including education and practical tips on allergens avoidance .Figure AR is a multi-factorial disease with a worldwide disabling effect on all individuals irrespective of age and ethnic background. In 2001 the ARIA in collaboration with the WHO workshop published guidelines for healthcare professionals in order to highlight the latest updates on the aetiology of AR emphasizing the association between AR and Asthma and proposing a management algorithm .Risk factors for AR include a combination of environmental and genetic interactions . The diaAn overwhelming 99% of UK ENT consultants use intra-nasal steroids to treat AR. This trend is supported by several studies demonstrating that intra-nasal steroids are the most efficacious and cost effective first line treatment for AR ,13.et al in a cochrane review showed sublingual immunotherapy to be a safe and effective option in managing AR [et al in a recently published meta-analysis advocate the use of allergen injection immunotherapy as an effective treatment with a low risk of adverse effects in the management of AR [Allergen specific immunotherapy for AR was first described in 1911 by Noon and involves the administration of a gradually increasing quantity of an allergen extract . Patientaging AR . Furthernt of AR . Howevernt of AR .The importance of educating patients or carers with advice leaflets with information regarding AR including allergen avoidance cannot be over emphasised and was actively supported by 78% of responders of this survey. This enables individuals to be actively involved in the management of their disease resulting in an overall improvement in patient satisfaction, treatment compliance and outcomes . Such prInterestingly, only 3% of otolaryngologists arranged pulmonary spirometry and 1% of all respondents referred AR patients to a respiratory physician for management of any associated lower respiratory tract pathology. Several studies though have demonstrated that AR patients with no underlying Asthma do have impaired pulmonary function and reversible airway obstruction ,22. In aThis survey demonstrates as expected a diverse approach to the management of Allergic Rhinitis. An interesting finding of the survey is that despite good evidence on the relationship between Asthma and AR, most otolaryngologists often do no think "outside the specialty", for example they would rarely use spirometry as a diagnostic aid.A combined treatment strategy of allergen avoidance, pharmacotherapy, immunotherapy and education applied to patients with AR and concomitant Asthma as recommended by the ARIA guidelines may reduce medical treatment costs and improve symptom control and quality of life.The authors declare that they have no competing interests.RSN: Primary Author of manuscript. PDK: Assistant Author of manuscript and Editing. EGT: Contribution to Literature Search and Proof Reading. AK: Senior Clinician and contribution to Proof Reading and Editing. DKN: Assisted writing manuscript and designing questionnaire. All authors read and approved the final manuscript.Dear colleague,Pease could you complete this survey with your responses and return it by clicking the SUBMIT button below. We thank you for your valuable time in completing this survey.1. Are you familiar with the association between Allergic Rhinitis and Asthma?• Yes• No2. Are you familiar with the Allergic Rhinitis and its impact on Asthma (ARIA) guidelines in collaboration with the World Health Organisation?• Yes• No3. What proportion of your patients with Allergic Rhinitis have got symptoms or diagnosis of Asthma?• <10%• 10 - 20%• 20 - 30%• 30 - 40%• 40 - 50%• >50%4. If you suspect Allergic Rhinitis what investigations would you consider ?• None• Skin prick test to known allergens• Serology tests e.g. RAST, IgE• Peak flow meter (air flow litres/minute)• Pulmonary spirometry5. If you suspect Allergic Rhinitis in a patient which of the following management plans would you consider?• Start treatment and review• Start treatment and discharge patient to GP for follow-up• Start treatment and refer to a Respiratory Physician6. If you suspect Allergic Rhinitis which of the following would you use for treatment ?• Antihistamine - oral• Antihistamine - intra-nasal• Steroid - intra-nasal• Steroid - intra-bronchial• Steroid - oral• Decongestant - oral• Decongestant - intra-nasal• Anti-cholinergic (Ipatropium Bromide)• Anti-leukotriene• Specific Immunotherapy - sublingual• Specific Immunotherapy - subcutaneous7. How long do you prescribe nasal sprays for• 3 months• 6 months• >6 months8. What is the frequency of nasal spray administration do you prescribe ?• Two puffs once a day• Two puffs twice a day• Other (please specify)9. Do you provide leaflets for patients about life-style changes including education and avoidance of allergen(s)?• Yes• NoThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6815/11/3/prepub


Due to theoretical importance of nuclear quadrupole resonance data [17O and 14N- NQR parameters. The studies reported in this work were undertaken to establish whether the NQR method could be used to derive a rational structure-activity relationship for these inhibitors. These findings open up useful applications for this family of inhibitors, considering the vast number of alternative disease related proteases that may exist.Increasing numbers of HIV infected patients along with severe treatment-associated complications and related deaths make the AIDS pandemic . These ince data  for char


A 29-year-old female patient with Ebstein anomaly was referred to our division for drug-resistant symptomatic wide-complex tachycardia. Her preprocedural electrocardiograms showed a sinus rhythm without delta wave and a wide-complex short RP tachycardia with a rate of 150 bpm during palpitation. During conventional electrophysiologic study earliest local activation times during the tachycardia were obtained from the right parahisian region . A few sTo the best of our knowledge, this is the first case whose parahisian atrial tachycardia was ablated from the aortic cusp using cryothermal energy. Cryoablation from the aortic cusps should be considered to ablate the arrhythmia focus when RFA threatens the normal conduction system or vital anatomical structures .


The interface between titanium dioxide and biological solution is relevant for the bioactivity of titanium implants. Adhesion phenomena between inorganic solids are of general interest for mineralization and bone formation processes.6 atoms in the 10-100 ns range and ab initio molecular dynamics wit 100-200 atoms for some ps.Such interfaces are complex systems with many constituents including the hydroxylated metal oxide support, hydrocarbon contamination, ionic water solution and a variety of biopolymers. Our computational methods comprise classical molecular dynamics with around 102 on Ti metal may be commensurate and crystalline [• Electronic structure calculations show that even very thin layers of TiOstalline . A varie2 is in practice screened by hydrocarbons, which may enhance inflammatory complications of implants [• The oxide is hydroxylated and its surface charge density correlates with the pH-value. The highly hydrophilic TiO• Sequence specific protein adsorption on inorganic surfaces was found in several experiments on inorganic surfaces, even though no key-lock mechanism is conceivable. We propose two effects : (i) Con• Close to solids water has an ordered structure, which only slightly depends on the surface charge density. These layers hinder protein adsorption. A major difference to the bulk is the reduced water mobility there.


The selection tool deriving from this analysis may allow an optimal use of the available treatment strategies in these patients.In radically resected gastric cancer the possibility to predict the site of relapse could be clinically relevant for the selection of post-surgical management. We previously showed that specific tumour integrins genotypes are independently associated with either peritoneal or hematogenous metastases (ITGA and ITGV). Recently VEGF and VEGF-R polymorphisms have been demonstrated to potentially affect tumour angiogenesis and the metastatic process in gastric cancer. We then investigated the role of VEGFs and VEGF-R genotyping in determining either peritoneal carcinosis or hematogenous metastases in radically resected gastric cancer patients. Tumour genotyping for integrins (ITGA and ITGV) was also performed according to our previous findings. Genotyping for VEGF-A, VEGF-C, VEGFR-1,2,3 and ITGA and ITGV was carried out on pT4a radically resected gastric tumours recurring with either peritoneal-only carcinosis or hematogenous metastases. 101 patients fulfilled the inclusion criteria: 57 with peritoneal carcinomatosis only and 44 with hematogenous spread only. At multivariate analysis, intestinal histology and the AC genotype of rs699947 (VEGFA) showed to independently correlate with hematogenous metastases (p = 0.0008 and 0.008 respectively), whereas diffuse histology and the AA genotype of rs2269772 (ITGA) independently correlated with peritoneal-only diffusion (p = <0.0001 and 0.03 respectively). Our results seem to indicate that combining information from genotyping of rs699947  The global outcome for radically resected gastric cancer patients remained substantially unchanged across the years in western Countries, with a 5-years survival rate ranging between 15% and 35% of all cases In western Countries only a modest survival benefit, has been observed for adjuvant chemotherapy mainly in pooled analyses and the beneficial effect of chemoradiotherapy seemed limited to patients receiving an inadequate clearance of the lymphatics Peritoneal carcinosis may be the first site of relapse in approximately 40 to 50% of patients undergoing radical resection ITGA) and rs11902171 (ITGV) may represent a critical asset in the definition of high risk gastric cancer patients for peritoneal carcinosis In a previous analysis we found that Genotyping of rs2269772  superfamily has been identified to critically influence angiogenesis in solid tumours. Published data suggest that in presence of tumour angiogenesis-related factors distant metastases are more likely to occur Interestingly it has been also demonstrated that the angiogenic phenotype may differ between intestinal-type and diffuse-type gastric cancer. In different analyses intestinal-type tumours seem in fact more biologically dependent on angiogenesis than diffuse-type tumours Single-nucleotide polymorphisms (SNPs) in the vascular endothelial growth factors (VEGF) and VEGF receptors (VEGF-R) genes have been correlated to tumour neoangiogenesis through different biological mechanisms. In patients with colorectal cancer specific SNPs in the VEGF-R2 have been shown to significantly influence microvessel density Tumour lymphangiogenesis is strictly dependent on the biological activity of the VEGFC and the VEGF-R3 Predicting the location of recurrence amongst high risk individuals may allow for tailored adjuvant approaches. We therefore examined the role of tumour VEGFs and VEGF-Rs polymorphisms in determining either peritoneal carcinosis or hematogenous metastases in radically resected gastric cancer patients. Clinical data and SNPs results for tumour VEGFs, VEGF-Rs and integrins have been analysed with the aim to suggest a biologically-driven profile to be employed as a tool for the appropriate treatment selection in the appropriate patient.th TNM.The patients study population was selected from a central database including patients affected by gastric cancer, operated in four different Institutions of our Region. Classification of the T, N and M-factors was made according to the numeric system introduced by the 7Only patients who had recurred within 2 years, with either peritoneal-only carcinosis or hematogenous metastases after curative gastrectomy for a pT4a gastric adenocarcinoma, who did not receive adjuvant chemotherapy and whose tumour specimen was available were selected for tumour genotyping. Patients with either distant metastases at the time of diagnosis or presence of exfoliated tumour cells in peritoneal lavage obtained during laparotomy were excluded from analysis. We decided to restrict our analysis to patients with pT4a tumours as this group of patients is at higher risk for peritoneal diffusion and is often considered for locoregional treatment such as intraperitoneal chemotherapy. However a not negligible proportion of these patients does not recur locally and therefore a selection tool in this setting would be a particularly valuable asset for the treating physicians. Since most recurrences are registered within 2 years from diagnosis we chose to exclude patients recurring after this time period in order to obtain an homogenous population.Follow-up of both groups  occurred at three-months intervals. Follow-up consisted of physical examination, a complete blood count, chest radiography and US of the abdomen or CT scanning as clinically indicated. The site and date of first relapse and the date of death were recorded.This study was approved by Ethical committee AOU Ospedali Riuniti – Umberto I of our institution. All patients provided informed written consent.VEGF and VEGF-R genotyping was performed on formalin-fixed paraffin-embedded tissue block (about 30 mg) of primary gastric cancer samples.Paraffin wax was removed with xylene and the samples were washed twice with 100% ethanol. DNA was isolated from the deparaffinised tissue using the RecoverAll™ Total Nucleic Acid Isolation Kit for FFPE Tissues , according to the manufacturer’s instructions. DNA from each sample was then eluted in 120 µl of eluting solution.http://pupasuite.bioinfo.cipf.es/index.jsf - version 2.0.0, bioinfo 2008), the CIPF Single Nucleotide Polymorphism database (dbSNP) generated by the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/SNP) and by review of the medical literature, using the following criteria:Single nucleotide polymorphisms (SNPs) within each gene were selected using the Pupasuite software ;the minor allele frequency was above 10% ;the genetic polymorphism was established and well-documented.Further considerations drove the selection of SNPs for our study. A correlation between the presence of a specific allele on a polymorphic site and the expression of the respective protein has been previously documented for VEGF Globally we assumed that selected SNPs had impact on protein expression and therefore on biological function.Selected SNPs were as follows: six polymorphisms in the VEGFA gene , two in VEGFC , two in VEGF-R1 (FLT1) , four in VEGF-R2 (KDR)  and three in VEGF-R3 (FLT4) . Chromosomal locations, positions and biological effects of investigated VEGF and VEGFR SNPs have been summarised in SNP genotyping was performed by TaqMan technology, using SNP genotyping products (Applied Biosystems). Polymerase chain reaction (PCR) was performed and genotypes were analysed on the 7300 Real-Time PCR System (Applied Biosystems) using an ABI Prism 7300 Sequence Detection System software . Each reaction contained 0.2 µl of total genomic DNA. Genotyping was performed by laboratory personnel blinded to patient status, and a random 10% of the samples were repeated to validate genotyping procedures.All SNPs genotyped had to present an overall call rates of ≥90% to be included in our analysis.ITGA and G and C genotypes of rs11902171, ITGV) was conducted as previously described Genotyping for tumour integrins independently associated with either peritoneal or hematogenous metastases in our previous analysis  and each VEGF and VEGF-R polymorphism.Tested variables included sex , age (<65 yrs vs. ≥ 65 yrs), absence or presence of lymph node metastases (pN0 vs. pN+), type of lymphadenectomy (D1 vs. D2), tumour histology according to Lauren’s classification , lymphatic/blood vessels invasion (presence vs. absence), the clinical Center where surgery was performed, integrins genotyping  in the 2 groups  was calculated with a 95% confidence interval. A significant level of 0.05 was chosen to assess the statistical significance.www.statgen.ncsu.edu/powermarker).All polymorphisms were examined for deviation from Hardy-Weinberg equilibrium using the Powermarker v. 3.25 package (www.statgen.ncsu.edu/powermarker). LD was estimated using r2, with r2 = 1 indicating complete LD and r2 = 0 indicating absent LD.Linkage Disequilibrium (LD) analysis was also performed using the Powermarker v. 3.25 package . Follow-up data were available for all patients included. Follow-up consisted of physical examination, a complete blood count, chest radiography and US of the abdomen or CT/MRI scanning as clinically indicated. Only patients who exclusively developed either peritoneal carcinosis or hematogenous metastases during the entire course of their disease were considered.All patients underwent radical surgery (R0) for pT4a gastric cancer, regional lymphnodes were negative for metastases (pN0) in 23 patients (23%). Most of the patients underwent a D2 lymphadenectomy . Pathology report showed intestinal histology in 51 cases (51%) and diffuse histology in 50 patients (49%) . Fifty-sAll SNPs genotyped presented an overall call rates of ≥90%.Repeated samples for genotyping validation confirmed results obtained by previous analysis in all cases.VEGFA), the AC genotype of rs699947 (VEGFA) and the GG genotype of rs7993418 (FLT1) resulted more prone to hematogenous metastases  (Gastric tumours showing the AA genotype of rs10434 (ctively) . No corrAnalysis of the remaining VEGF and VEGF-R polymorphisms did not show any correlation with either peritoneal carcinosis or hematogenous metastases .Globally results for tumour integrins genotyping confirmed our previous findings.ITGA) resulted less prone to peritoneal carcinosis , whereas the AA genotype of rs2269772 (ITGA) was more frequently associated to peritoneal carcinosis . The CC genotype of rs11902171 (ITGV) was more frequently associated to peritoneal carcinosis . On the contrary, patients with the GG genotype of rs11902171 in the ITGV gene developed peritoneal carcinosis less frequently than hematogenous metastases .Patients tumours with the GG genotype of rs2269772 , whereas tumour intestinal histology was linked to hematogenous metastases  .At multivariate analysis, intestinal histology and the AC genotype of rs699947 (VEGFA) showed to independently correlate with hematogenous metastases, whereas diffuse histology and the AA genotype of rs2269772 (ITGA3) independently correlated with peritoneal-only diffusion (p = 0.001). Odds ratio results for these latter factors confirmed their role in guiding tumour cells through the metastatic process toward the peritoneum or hematogenous sites .The introduction of multiple therapeutic options for the post-surgical management of radically resected gastric cancer patients has opened the question of optimal patients selection. Unfortunately a critical limiting factor for the potential of these treatment choices is represented by the lacking of clinical and biological factors able to predict the site of recurrence. The containment of disease with a locoregional treatment such as intraperitoneal chemotherapy may be in fact inadequate in patients at high risk for hematogenous metastases and should be better reserved to patients most likely to recur with peritoneal-only diffusion. On the other hand in patients more likely to recur with hematogenous metastases adjuvant chemotherapy may represent a more effective strategy.In our experience the rs699947  polymorphism is independently related to a higher risk of hematogenous metastasis with an OR 8.08 . SNPs in the promoter region of the VEGF gene have been already demonstrated to affect patients outcome in colorectal, breast and gastric cancer As previously described the rs2269772  genotype of tumour integrins confirmed to be independently relevant in determining peritoneal diffusion of gastric cancer cells [10). This finding deriving from a multivariate analysis including tumour-angiogenesis related factors strongly suggests that this specific tumour integrin polymorphism should be considered in future studies. On the contrary our analysis could not confirm the role of tumour integrins in determining hematogenous diffusion. We know from previously published analyses that upregulation of integrins sub-classes could enhance neoplastic cells motility and VEGF expression Tumour histology resulted a further factor independently able to identify the gastric cancer potential to determine either peritoneal or hematogenous metastases. Nonetheless tumour histology alone does not seem sufficient to accurately predict the metastatic sites. In our experience, similarly to previous reports, a relevant proportion of patients developed peritoneal carcinosis or hematogenous metastases independently from tumour histology. Similar considerations could be applied to the presence of tumour serosal involvement and/or exfoliated cancer cells in peritoneal lavage. Not all gastric tumours with serosal infiltration will eventually develop carcinosis and a negative peritoneal lavage unfortunately does not exclude a future peritoneal diffusion Globally we believe that genotyping for specific VEGFA and integrin genes may represent a critical asset in the definition of the metastatic diffusion for radically resected gastric cancer patients. Radically resected gastric cancer patients at high risk for peritoneal recurrence may be optimal candidates for intraperitoneal therapy, whereas if the risk of hematogenous metastases is predominant systemic chemotherapy may represent a better option. The selection tool deriving from this analysis may then allow an optimal use of the available treatment strategies and should represent a possible stratification factor in future studies in these patients.


The neonatal Fc receptor (FcRn) binds immunoglobulin G (IgG), protects it from degradation and can transport IgG from apical to basolateral side of epithelial cells . Previou2 were used for subsequent experiments. Monoclonal IgG was added either apically or basolaterally and after incubation IgG was measured in the culture supernatant using an ELISA that was developed inhouse. To distinguish leakage of IgG through the cell layer from active transport by the cells we used NH4Cl or Chloroquine to block cytoplasmic vesicles.Monolayers of RPE cells, ARPE-19  and human primary RPE cells , were established on Transwell culture inserts using fibronectin coated membranes. Trans-epithelial resistance (TER) measurements were used to evaluate monolayer formation. Plates with an average TER >35Ω*cm4Cl and Chloroquine were limited.The highest TERs were observed with ARPE-19 cells, while TERs often remained low with the primary cell cultures. The IgG level that crossed the membrane correlated positively incubation time, but this association was not linear. The observed effects of NHFurther experiments are needed to determine whether there is active transport by the RPEs. Paracellular diffusion will be investigated using dextran and specific blocking antibodies for the FcRn. In addition, experiments will be performed with RPE cells where FcRn is overexpressed or knocked-out.


Balloon dilatational percutaneous tracheostomy with radial outward dilation minimizes bleeding and injury to tracheal rings . Using tTwenty-five patients including 15 males and 10 females, mean age 61 years, with age range from 23 to 102 years, underwent bedside percutaneous tracheostomy combining real-time ultrasound and the Blue Dolphin technique.The median time for the procedure was 15 (12 to 20) minutes. Targeted placement for the tracheostoma between the second and third or the third and fourth tracheal ring was achieved in 100%. No significant complications  occurred. One fractured tracheal ring was identified using bronchoscopy after the procedure. No conversion into a bronchoscopically guided or into a surgical open technique was necessary.This study demonstrates the feasibility and safeness combining real-time ultrasound guidance and balloon dilatational percutaneous tracheostomy (Blue Dolphin technique) in critically ill patients. In our division, this technique has become the standard bedside tracheostomy procedure because it combines excellent patient safety features with avoidance of intraprocedural tube misplacement, hypoventilation and accidental bronchoscopy damage even in technically difficult cases .


The discovery of neutralizing antibodies that are broadly reactive with multiple influenza subtypes is therefore extremely important for the influenza pandemic preparedness, for use either for therapeutic purposes or as the basis of vaccine development. On the other hand, recently studies also suggest that cell-mediated immunity might be critical for cross-subtype protection against influenza virus infection. Using vaccinia virus-based H5 vaccine, we also demonstrated this approach might also capable of inducing cross-subtype protection. Mice received this H5 vaccine had no detectable neutralization antibody against other HA subtypes, suggesting that cell-mediated immunity might be account for the subtype protection. Here, we would discuss our recent findings on these research topics.The continuous antigenic drifts and occasional antigenic shifts enable human influenza viruses to escape the human immune system. Moreover, the frequent occurrence of human H5N1-infected cases and the recent emergency of a novel swine-like human H1N1 influenza virus further reiterate the risk of the introduction of a new pandemic strain to humans through