A Killian-Jamieson diverticulum is a 'false' diverticulum on the lateral side of the proximal cervical esophagus. They are much rarer than Zenker diverticula and can be difficult to diagnose. They ...are best visualized using fluoroscopy studies, however, the workup for patients admitted with dysphagia can be sometimes extensive and unnecessary, leading to costly hospital stays, longer admissions and exposure to excessive radiation. Herein, we present a patient previously diagnosed with a Killian Jamieson diverticulum, who presented with worsening dysphagia, odynophagia and neck swelling, and was found to have an unusual inferior extension of the diverticulum. This paper will recognize the role of fluoroscopy in diagnosing diverticula and identifying causes of dysphagia, and to also recognize the use of American College of Radiology 'ACR' Appropriateness Criteria to minimize unnecessary studies.
The Barrovian metamorphism of the Lepontine dome is manifested by isograds that cross‐cut tectonic nappe contacts, which is commonly interpreted as metamorphism that occurred after nappe emplacement. ...However, the pervasive mineral and stretching lineation in amphibolite facies, associated with top‐to‐foreland shearing, suggests that peak Barrovian conditions are coeval with nappe‐overthrusting. Here, we combine mapping and U‐Pb zircon dating to better constrain the relation between metamorphism and overthrusting. Metamorphic zircon rims show two age populations at 31–33 and 22–24 Ma. The younger population is locally observed in post‐foliation dikes (and associated metasomatism) likely sourced from deep‐migmatites exhuming along the Alpine backstop. The older population occurs regionally and is found in syn‐kinematic migmatites which occur along a crustal‐scale shear zone. Below this shear zone, magmatic and detrital zircon cores suggest that the Cima Lunga unit, previously interpreted as a tectonic mélange with Mesozoic fragments, was a pre‐Variscan metasedimentary sequence intruded by Permian granitic sills, now orthogneisses. This unit was strongly sheared along the top of the Simano nappe during overthrusting of a rock pile here‐termed Maggia‐Adula nappe. This large‐scale nappe emplacement imprinted the regional lineation and peak temperatures until 31–33 Ma. Péclet (1–10) and Brinkman (0.002–1.8) numbers, estimated for the overthrusting, suggest an advection‐dominated heat transfer caused by rock exhumation, with some diffusion (conduction) during nappe emplacement. Diffusion contributed to Barrovian isograds discordant to the thrust. Shear heating was important if stress times shearing rate >∼5·10−6 W·m−3 within the nappe. The thermal evolution after overthrusting was spatially heterogeneous until ca. 22 Ma.
Plain Language Summary
The Lepontine area constitutes the core of the Central European Alps. It has a dome structure and it is internally formed by rock units which register pressure and temperature conditions typical of collisional orogens. The temperatures recorded by minerals are high and the origin of the heat that affected the Lepontine units is still unclear. In this study, we implemented different branches of geology to reveal the age of the Alpine events which juxtaposed the Lepontine units, their provenance and evolution. We performed extensive geological mapping to define the lithologies and structures of rocks. From 13 samples, we extracted 1158 zircon crystals that we analyzed and dated. Fieldwork permitted us to discover new rock units and better characterize the transition between the large‐scale units constituting the Lepontine dome. We propose a geodynamic scenario involving a major large‐scale Alpine unit. The emplacement of this unit generated the main heating event at 31–33 Ma, which is widespread and resulted in peak temperature conditions. The thermal evolution after this event was regionally complex and spatially heterogeneous. Locally in the south we document magmatic/fluid injections at 22–24 Ma, which were sourced from still‐hot regions in the roots of the orogen.
Key Points
Geological mapping reveals widespread syn‐tectonic migmatitic rocks along a main crustal‐scale shear zone inside the Lepontine dome
Alpine nappe emplacement is regionally recorded at 31–33 Ma, locally overprinted in the south by magmatic/fluid pulses at 22–24 Ma
Mapping and detrital zircon crystals suggest a structurally coherent Cima Lunga unit of pre‐Variscan age, as part of the Simano nappe
Therapies that produce deep and durable responses in patients with metastatic melanoma are needed. This phase II cohort from the international, single-arm PIVOT-02 study evaluated the ...CD122-preferential interleukin-2 pathway agonist bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) in first-line metastatic melanoma.
A total of 41 previously untreated patients with stage III/IV melanoma received BEMPEG 0.006 mg/kg plus NIVO 360 mg once every 3 weeks for ≤ 2 years; 38 were efficacy-evaluable (≥ 1 postbaseline scan). Primary end points were safety and objective response rate (blinded independent central review); other end points included progression-free survival, overall survival (OS), and exploratory biomarkers.
At 29.0 months' median follow-up, the objective response rate was 52.6% (20 of 38 patients), and the complete response rate was 34.2% (13 of 38 patients). Median change in size of target lesions from baseline was -78.5% (response-evaluable population); 47.4% (18 of 38 patients) experienced complete clearance of target lesions. Median progression-free survival was 30.9 months (95% CI, 5.3 to not estimable). Median OS was not reached; the 24-month OS rate was 77.0% (95% CI, 60.4 to 87.3). Grade 3 and 4 treatment-related and immune-mediated adverse events occurred in 17.1% (7 of 41) and 4.9% (2 of 41) of patients, respectively. Increased polyfunctional responses in CD8+ and CD4+ T cells were seen in blood after treatment, driven by cytokines with effector functions. Early on-treatment blood biomarkers (CD8+ polyfunctional strength difference and eosinophils) correlated with treatment response.
BEMPEG in combination with NIVO was tolerated, with relatively low rates of grade 3 and 4 treatment-related and immune-mediated adverse events. The combination had encouraging antitumor activity in first-line metastatic melanoma, including an extended median progression-free survival. Exploratory analyses associated noninvasive, on-treatment biomarkers with response, before radiologic evidence was observed.
This work discusses the significance of particular types of soft-sediment deformations very common within turbidite deposits, namely convolute laminations and load structures.
Detailed facies ...analyses of the foredeep turbidites in the Marnoso-arenacea Formation (northern Italy) and Annot Sandstones (south eastern France) show that these deformational structures tend to increase near morphological obstacles, concomitantly with contained-reflected beds. The lateral and vertical distribution of convolute laminae and load structures, as well as their geometry, has a well-defined depositional logic related to flow decelerations and reflections against bounding slopes. This evidence suggests an interaction between fine-grained sediment and the presence of morphologic relief, and impulsive and cyclic-wave loadings, which are produced by flow impacts or reflected bores and internal waves related to impinging bipartite turbidity currents.
•The significance of convolute laminations and load structures in turbidites has been discussed.•Convolute laminae are related to flow reflections against bounding slopes.•Basal load casts are related to decelerations of high-density flows against bounding slopes.•Contained-reflected beds and convolute laminae increase consistently with synsedimentary-structural uplifts.•Lateral–vertical distribution of these soft-sediment deformations depends on basin morphology.
A seeded FEL driven by a linac based on super conducting cavities, generating 108-1010 coherent photons per shot at 2-5 keV with 0.2-1 MHz of repetition rate, can address the need of a source devoted ...to fine analysis of matter using the linear spectroscopy technique. The seeding scheme described hereafter is a multi-stage cascade upshifting the radiation frequency by a factor 20-40. The x-ray range can be achieved with a seed constituted by a coherent flash in the extreme ultraviolet range provided by an FEL oscillator operating at 12-14 nm. The whole chain of x-ray generation is described by means of start-to-end three-dimensional simulations.
Interleukin-2 (IL-2) is integral to immune system regulation. Its opposing immunostimulatory and immunosuppressive actions make it an attractive therapeutic target for cancer and autoimmune diseases. ...A challenge in developing IL-2-directed anticancer therapies has been how to stimulate effector T cells (Teffs) without inducing regulatory T cells (Tregs) in the tumor microenvironment; conversely, IL-2 therapy for autoimmune diseases requires Treg induction without further stimulation of Teffs. High-dose IL-2 is approved for melanoma and renal cell carcinoma, but its therapeutic value is limited by a need for frequent dosing at specialist centers, its short half-life, severe toxicity, and a lack of efficacy in most patients. Re-engineered IL-2 therapeutics are designed to have longer in vivo half-lives, target specific IL-2 receptor conformations to stimulate specific T cell subsets, or localize to target tissues to optimize efficacy and reduce toxicity. We discuss recent studies that elucidate the potential of newly engineered IL-2-based therapeutics for cancer and autoimmune diseases.
Background and purpose
Studies investigating psychological interventions for the promotion of well‐being in people with amyotrophic lateral sclerosis (ALS) are lacking. The purpose of the current ...study was to examine the use of an ALS‐specific mindfulness‐based intervention for improving quality of life in this population.
Methods
A randomized, open‐label and controlled clinical trial was conducted on the efficacy of an ALS‐specific meditation programme in promoting quality of life. Adults who received a diagnosis of ALS within 18 months were randomly assigned either to usual care or to an 8‐week meditation training based on the original mindfulness‐based stress reduction programme and tailored for people with ALS. Quality of life, assessed with the ALS‐Specific Quality of Life Revised scale, represented the primary outcome, whilst secondary outcomes included anxiety and depression, assessed with the Hospital Anxiety and Depression Scale, and specific quality of life domains. Participants were assessed at recruitment and after 2, 6 and 12 months. The efficacy of the treatment was assessed on an intention‐to‐treat basis of a linear mixed model.
Results
A hundred participants were recruited between November 2012 and December 2014. Over time, there was a significant difference between the two groups in terms of quality of life (β = 0.24, P = 0.015, d = 0.89). Significant differences between groups over time were also found for anxiety, depression, negative emotions, and interaction with people and the environment.
Conclusions
An ALS‐specific meditation programme is beneficial for the quality of life and psychological well‐being of people with ALS.
BackgroundImmune checkpoint inhibitor-based combinations have expanded the treatment options for patients with renal cell carcinoma (RCC); however, tolerability remains challenging. The aim of this ...study was to evaluate the safety and efficacy of the immunostimulatory interleukin-2 cytokine prodrug bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) as first-line therapy in patients with advanced clear-cell RCC.MethodsThis was an open-label multicohort, multicenter, single-arm phase 1/2 study; here, we report results from the phase 1/2 first-line RCC cohort (N=49). Patients received BEMPEG 0.006 mg/kg plus NIVO 360 mg intravenously every 3 weeks. The primary objectives were safety and objective response rate (ORR; patients with measurable disease at baseline and at least one postbaseline tumor response assessment). Secondary objectives included overall survival (OS) and progression-free survival (PFS). Exploratory biomarker analyses: association between baseline biomarkers and ORR.ResultsAt a median follow-up of 32.7 months, the ORR was 34.7% (17/49 patients); 3/49 patients (6.1%) had a complete response. Of the 17 patients with response, 14 remained in response for >6 months, and 6 remained in response for >24 months. Median PFS was 7.7 months (95% CI 3.8 to 13.9), and median OS was not reached (95% CI 37.3 to not reached). Ninety-eight per cent (48/49) of patients experienced ≥1 treatment-related adverse event (TRAE) and 38.8% (19/49) had grade 3/4 TRAEs, most commonly syncope (8.2%; 4/49) and increased lipase (6.1%; 3/49). No association between exploratory biomarkers and ORR was observed. Limitations include the small sample size and single-arm design.ConclusionsBEMPEG plus NIVO showed preliminary antitumor activity as first-line therapy in patients with advanced clear-cell RCC and was well tolerated. These findings warrant further investigation.
Inhibitor development is influenced by several factors and the type of factor VIII (FVIII) products may play a role.
In order to explore such a role, we designed a cohort study whose novelty resides ...in the classification of products not only according to the source of FVIII (plasmatic, pd, or recombinant, r) but also to their degree of purity (expressed as specific activity).
Treatment data up to inhibitor development or 150 exposure days were collected in 377 patients with hemophilia A.
Inhibitors developed in 111 patients (29%; 96 high-responders, 25%). The cumulative incidence was progressively higher from patients treated with low/intermediate-purity pdFVIII compared with those treated with high-purity pd and rFVIII. The adjusted hazard ratio of inhibitor development was 4.9 with rFVIII and 2.0 with high-purity pdFVIII (95% CI, 2.9-8.3 and 1.1-4.0), taking as reference low/intermediate-purity pdFVIII. There was no difference in the frequency of inhibitor testing between treatment groups. Sensitivity analyses (in patients who never switched product type, previously untreated patients, those treated on-demand and those with high-risk F8 mutations) confirmed an increased inhibitor risk with rFVIII and high-purity pdFVIII.
This study shows that the degree of purity of FVIII products influences inhibitor development independently from other risk factors, and emphasizes that differences exist within pdFVIII products.
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