PD‐1 inhibition in congenital pigment synthesizing metastatic melanoma

A newborn female child was born with a congenital pigment synthesizing melanoma of the scalp. Further workup revealed metastatic disease within the liver, lungs, and left tibia. Whole exome sequencing was performed on multiple samples that revealed one somatic mutation, lysine methyltransferase 2C (KMT2C), at low allelic frequency but no v‐Raf murine sarcoma viral oncogene homolog B (BRAF), NF‐1 mutation. Programmed death ligand 1 was moderately expressed. Treatment was initiated with the programmed cell death protein 1 inhibitor nivolumab. The patient tolerated this treatment well with minimal toxicity. She is now over a year out from initial diagnosis, continuing on nivolumab, with stable disease.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139985/1/pbc26702.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139985/2/pbc26702_am.pd

An Investigation into the Measurement and Prediction of Mechanical Stiffness of Lower-limb Prostheses used for Running

Two energy return prosthesis are subjected to three different statically applied loading methods. This initial study proposes that statically applied loading to a sport prosthesis using several controlled methods were statistically robust enough to derive a mechanical stiffness value. However, any predicted stiffness is drawn into question when allowing any movement of the distal end. This uncertainty will make any evaluation or prescription of lower-limb prosthesis technology based upon their stiffness incorrect. In addition, the peak calculated stiffness at the expected bodyweight induced ground impact load of a runner is judged the most representative assessment method. This study attempts to build on previous research advocating the need to monitor the performance of prosthesis lower-limb technology in disability sport. Practitioner Summary: This paper extends previous research regarding the fairness of prosthetics technology used in running with a lower-limb amputation. It pilots a quantitative assessment of high activity prosthetics technology and ultimately demonstrates how incorrect assessment can lead to incorrect specification of running prosthesis for elite level spor

Tissue and serum markers of inflammation during the follow-up of patients with giant-cell arteritis—a prospective longitudinal study

Objective. To evaluate the association between inflammatory markers and relapse in GCA patients longitudinally assessed in a clinical trial of infliximab and glucocorticosteroids

Stem-like CD4+T Cells in Perivascular Tertiary Lymphoid Structures Sustain Autoimmune Vasculitis

Autoimmune vasculitis of the medium and large elastic arteries can cause blindness, stroke, aortic arch syndrome, and aortic aneurysm. The disease is often refractory to immunosuppressive therapy and progresses over decades as smoldering aortitis. How the granulomatous infiltrates in the vessel wall are maintained and how tissue-infiltrating T cells and macrophages are replenished are unknown. Single-cell and whole-tissue transcriptomic studies of immune cell populations in vasculitic arteries identified a CD4+ T cell population with stem cell-like features. CD4+ T cells supplying the tissue-infiltrating and tissue-damaging effector T cells survived in tertiary lymphoid structures around adventitial vasa vasora, expressed the transcription factor T cell factor 1 (TCF1), had high proliferative potential, and gave rise to two effector populations, Eomesodermin (EOMES)+ cytotoxic T cells and B cell lymphoma 6 (BCL6)+ T follicular helper-like cells. TCF1hiCD4+ T cells expressing the interleukin 7 receptor (IL-7R) sustained vasculitis in serial transplantation experiments. Thus, TCF1hiCD4+ T cells function as disease stem cells and promote chronicity and autonomy of autoimmune tissue inflammation. Remission-inducing therapies will require targeting stem-like CD4+ T cells instead of only effector T cells

Large-scale geo-facial image analysis

While face analysis from images is a well-studied area, little work has explored the dependence of facial appearance on the geographic location from which the image was captured. To fill this gap, we constructed GeoFaces, a large dataset of geotagged face images, and used it to examine the geo-dependence of facial features and attributes, such as ethnicity, gender, or the presence of facial hair. Our analysis illuminates the relationship between raw facial appearance, facial attributes, and geographic location, both globally and in selected major urban areas. Some of our experiments, and the resulting visualizations, confirm prior expectations, such as the predominance of ethnically Asian faces in Asia, while others highlight novel information that can be obtained with this type of analysis, such as the major city with the highest percentage of people with a mustache

A candidate ion-retaining state in the inward-facing conformation of sodium/galactose symporter: Clues from atomistic simulations

The recent Vibrio parahaemolyticus sodium/galactose (vSGLT) symporter crystal structure captures the protein in an inward-facing substrate-bound conformation, with the sodium ion placed, by structural alignment, in a site equivalent to the Na2 site of the leucine transporter (LeuT). A recent study, based on molecular dynamics simulations, showed that the sodium ion spontaneously leaves its initial position diffusing outside vSGLT, toward the intracellular space. This suggested that the crystal structure corresponds to an ion-releasing state of the transporter. Here, using metadynamics, we identified a more stable Na+ binding site corresponding to a putative ion-retaining state of the transporter. In addition, our simulations, consistently with mutagenesis studies, highlight the importance of D189 that, without being one of the NA(+)-coordinating residues, regulates its binding/release

Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin

Pathological processes involved in the initiation of rheumatoid synovitis remain unclear. We undertook the present study to identify immune and stromal processes that are present soon after the clinical onset of rheumatoid arthritis ( RA) by assessing a panel of T cell, macrophage, and stromal cell related cytokines and chemokines in the synovial fluid of patients with early synovitis. Synovial fluid was aspirated from inflamed joints of patients with inflammatory arthritis of duration 3 months or less, whose outcomes were subsequently determined by follow up. For comparison, synovial fluid was aspirated from patients with acute crystal arthritis, established RA and osteoarthritis. Rheumatoid factor activity was blocked in the synovial fluid samples, and a panel of 23 cytokines and chemokines measured using a multiplex based system. Patients with early inflammatory arthritis who subsequently developed RA had a distinct but transient synovial fluid cytokine profile. The levels of a range of T cell, macrophage and stromal cell related cytokines ( e. g. IL-2, IL-4, IL-13, IL-17, IL-15, basic fibroblast growth factor and epidermal growth factor) were significantly elevated in these patients within 3 months after symptom onset, as compared with early arthritis patients who did not develop RA. In addition, this profile was no longer present in established RA. In contrast, patients with non-rheumatoid persistent synovitis exhibited elevated levels of interferon-gamma at initiation. Early synovitis destined to develop into RA is thus characterized by a distinct and transient synovial fluid cytokine profile. The cytokines present in the early rheumatoid lesion suggest that this response is likely to influence the microenvironment required for persistent RA

Rheumatoid Arthritis is an Autoimmune Disease Triggered by Proteus Urinary Tract Infection

Rheumatoid arthritis (RA) is a chronic and disabling polyarthritic disease, which affects mainly women in middle and old age

Does maximising ball speed in cricket fast bowling necessitate higher ground reaction forces?

This is an Accepted Manuscript of an article published by Taylor & Francis in Journal of Sports Sciences on 17th July 2015, available online: http://www.tandfonline.com/10.1080/02640414.2015.1069375.This study aimed to investigate whether high peak ground reaction forces and high average loading rates are necessary to bowl fast. Kinematic and kinetic bowling data were collected for 20 elite male fast bowlers. A moderate non-significant correlation was found between ball speed and peak vertical ground reaction force with faster bowlers tending to have lower peak vertical ground reaction force (r = −0.364, P = 0.114). Faster ball speeds were correlated with both lower average vertical and lower average horizontal loading rates (r = −0.452, P = 0.046 and r = −0.484, P = 0.031, respectively). A larger horizontal (braking) impulse was associated with a faster ball speed (r = 0.574, P = 0.008) and a larger plant angle of the front leg (measured from the vertical) at front foot contact was associated with a larger horizontal impulse (r = 0.706, P = 0.001). These findings suggest that there does not necessarily need to be a trade-off between maximum ball release speed and the forces exerted on fast bowlers (peak ground reaction forces and average loading rates). Furthermore, it appears that one of the key determinants of ball speed is the horizontal impulse generated at the ground over the period from front foot contact until ball release