Explore the vast range of titles available.

INTRODUCTION:Ischemic Colitis (IC) is the most common form of intestinal ischemic disorders. This disease process typically affects older adults and is the result of non-occlusive hypoperfusion, which can be precipitated by a multitude of risk factors. Patients usually present with lower abdominal pain and hematochezia. A colonoscopy with biopsies is the gold standard for diagnosis. Increasingly, medications have been associated with contributing to this disease process. Here, we report a unique case of IC attributed to Docetaxel, a taxane class chemotherapeutic agent.CASE DESCRIPTION/METHODS:A 76-year-old Caucasian female with a history of multi-focal intraductal carcinoma (Stage IIA), hypertension, and diverticulosis presented to the emergency room (ER) with complaints of lower back and abdominal pain. She had begun therapy with Docetaxel and Cyclophosphamide 8 days prior to presentation. In the ER, she was afebrile, neutropenic (ANC 400), and hypotensive requiring supportive care including antibiotics, fluids and a very brief course of norepinephrine. She was subsequently admitted to the intensive care unit where her neutropenia was noted to have resolved and antibiotics were discontinued in setting of negative cultures. On hospital day 3, she complained of continued abdominal pain and hematochezia with CT imaging that demonstrated bowel wall thickening and mild inflammatory changes in the sigmoid/descending colon. Subsequently, a colonoscopy was performed and showed circumferential, violaceous mucosa consistent with IC. Antibiotics were restarted and the patient was treated supportively with complete resolution of symptoms. Following hospital discharge, she was evaluated by her oncologist who discontinued her Docetaxel and initiated therapy with Paclitaxel. No recurrence of her symptoms have been noted and repeat cross sectional imaging demonstrated resolution of colonic thickening in the previously noted watershed distribution.DISCUSSION:IC is a rare but serious complication that has been described in patients receiving Docetaxel. Among the 6 reported cases, symptoms occur within 10 days of Docetaxel administration. Patients present with abdominal pain and hematochezia in the setting of neutropenia with or without fever. This type of IC is often severe, with spontaneous perforation, bowel necrosis, and a reported mortality rate of 40-50%. Although underreported, Docetaxel use is a risk factor for developing IC, one deserving of more clinical awareness.

INTRODUCTION:Anorectal sources account for 15–20% of hospital admissions for acute lower gastrointestinal bleeding (LGIB). Rectal varices are common in patients with portal hypertension, however, clinically significant bleeding occurs in only 0.5–5%. Management of rectal varices is described in several case reports but no standardized therapy exists due to the low incidence. Here we describe a case rectal varices treated by collateral vein embolization during an initial presentation for noncirrhotic hepatocellular carcinoma.CASE DESCRIPTION/METHODS:A 69-year-old African American male presented for weakness in the setting of 3 days of hematochezia. Medical history was notable for prostate cancer status post radiation therapy, prior hepatitis B exposure and hepatitis C status post Harvoni with sustained virologic response. Physical examination was notable for normal vital signs and gross blood on glove during rectal exam. Labs revealed a hemoglobin of 11.6 g/dl, and BUN of 18.0 mg/dl. CT abdomen was performed and notable for asymmetric rectal wall thickening, an ill-defined mass at the hepatic dome and expansion of the portal veins. He was admitted for colonoscopy in the setting of hematochezia. Liver MRI was completed, showing an abnormal heterogeneous right hepatic lobe with extensive portal vein thrombus and a 1.1 cm exophytic nodular LI-RADS 5 lesion. Tumor markers were notable for a normal CEA, and an Alpha-1-fetoprotein of >55,000 ng/ml. Colonoscopy was performed to evaluate the rectal findings on CT, revealing large rectal varices with a prominent nipple sign. Interventional radiology (IR) was consulted for embolization of a venous shunt draining bilateral hemorrhoidal veins and obtained a liver biopsy, resulting in grade II-III Hepatocellular carcinoma (HCC). Patient would ultimately fail sorafenib and lenvatinib therapy due to liver toxicity and continued tumor growth without recurrence of LGIB.DISCUSSION:HCC in the absence of cirrhosis has been documented in several patient populations to include chronic hepatitis B and more recently NASH. Portal vein thrombosis (PVT) is common in HCC with an incidence of 34–50%, and frequently leads to varix formation. Rectal varices are less common than esophageal and gastric varices, however can still result in life threatening hemorrhage. Given the low incidence, there are no established guidelines to define management strategies for bleeding rectal varices. Currently long term management is directed by physician expertise and available services.

People with chronic tetraplegia, due to high-cervical spinal cord injury, can regain limb movements through coordinated electrical stimulation of peripheral muscles and nerves, known as functional electrical stimulation (FES). Users typically command FES systems through other preserved, but unrelated and limited in number, volitional movements (eg, facial muscle activity, head movements, shoulder shrugs). We report the findings of an individual with traumatic high-cervical spinal cord injury who coordinated reaching and grasping movements using his own paralysed arm and hand, reanimated through implanted FES, and commanded using his own cortical signals through an intracortical brain–computer interface (iBCI). We recruited a participant into the BrainGate2 clinical trial, an ongoing study that obtains safety information regarding an intracortical neural interface device, and investigates the feasibility of people with tetraplegia controlling assistive devices using their cortical signals. Surgical procedures were performed at University Hospitals Cleveland Medical Center (Cleveland, OH, USA). Study procedures and data analyses were performed at Case Western Reserve University (Cleveland, OH, USA) and the US Department of Veterans Affairs, Louis Stokes Cleveland Veterans Affairs Medical Center (Cleveland, OH, USA). The study participant was a 53-year-old man with a spinal cord injury (cervical level 4, American Spinal Injury Association Impairment Scale category A). He received two intracortical microelectrode arrays in the hand area of his motor cortex, and 4 months and 9 months later received a total of 36 implanted percutaneous electrodes in his right upper and lower arm to electrically stimulate his hand, elbow, and shoulder muscles. The participant used a motorised mobile arm support for gravitational assistance and to provide humeral abduction and adduction under cortical control. We assessed the participant's ability to cortically command his paralysed arm to perform simple single-joint arm and hand movements and functionally meaningful multi-joint movements. We compared iBCI control of his paralysed arm with that of a virtual three-dimensional arm. This study is registered with ClinicalTrials.gov, number NCT00912041. The intracortical implant occurred on Dec 1, 2014, and we are continuing to study the participant. The last session included in this report was Nov 7, 2016. The point-to-point target acquisition sessions began on Oct 8, 2015 (311 days after implant). The participant successfully cortically commanded single-joint and coordinated multi-joint arm movements for point-to-point target acquisitions (80–100% accuracy), using first a virtual arm and second his own arm animated by FES. Using his paralysed arm, the participant volitionally performed self-paced reaches to drink a mug of coffee (successfully completing 11 of 12 attempts within a single session 463 days after implant) and feed himself (717 days after implant). To our knowledge, this is the first report of a combined implanted FES+iBCI neuroprosthesis for restoring both reaching and grasping movements to people with chronic tetraplegia due to spinal cord injury, and represents a major advance, with a clear translational path, for clinically viable neuroprostheses for restoration of reaching and grasping after paralysis. National Institutes of Health, Department of Veterans Affairs.

Versatile and precise genome modifications are needed to create a wider range of adoptive cellular therapies 1 – 5 . Here we report two improvements that increase the efficiency of CRISPR–Cas9-based genome editing in clinically relevant primary cell types. Truncated Cas9 target sequences (tCTSs) added at the ends of the homology-directed repair (HDR) template interact with Cas9 ribonucleoproteins (RNPs) to shuttle the template to the nucleus, enhancing HDR efficiency approximately two- to fourfold. Furthermore, stabilizing Cas9 RNPs into nanoparticles with polyglutamic acid further improves editing efficiency by approximately twofold, reduces toxicity, and enables lyophilized storage without loss of activity. Combining the two improvements increases gene targeting efficiency even at reduced HDR template doses, yielding approximately two to six times as many viable edited cells across multiple genomic loci in diverse cell types, such as bulk (CD3 + ) T cells, CD8 + T cells, CD4 + T cells, regulatory T cells (Tregs), γδ T cells, B cells, natural killer cells, and primary and induced pluripotent stem cell-derived 6 hematopoietic stem progenitor cells (HSPCs). Precise genome editing is made more efficient by stabilizing Cas9 and enhancing shuttling to the nucleus.

Soil property and class maps for the continent of Africa were so far only available at very generalised scales, with many countries not mapped at all. Thanks to an increasing quantity and availability of soil samples collected at field point locations by various government and/or NGO funded projects, it is now possible to produce detailed pan-African maps of soil nutrients, including micro-nutrients at fine spatial resolutions. In this paper we describe production of a 30 m resolution Soil Information System of the African continent using, to date, the most comprehensive compilation of soil samples ( N ≈ 150 , 000 ) and Earth Observation data. We produced predictions for soil pH, organic carbon (C) and total nitrogen (N), total carbon, effective Cation Exchange Capacity (eCEC), extractable—phosphorus (P), potassium (K), calcium (Ca), magnesium (Mg), sulfur (S), sodium (Na), iron (Fe), zinc (Zn)—silt, clay and sand, stone content, bulk density and depth to bedrock, at three depths (0, 20 and 50 cm) and using 2-scale 3D Ensemble Machine Learning framework implemented in the mlr (Machine Learning in R) package. As covariate layers we used 250 m resolution (MODIS, PROBA-V and SM2RAIN products), and 30 m resolution (Sentinel-2, Landsat and DTM derivatives) images. Our fivefold spatial Cross-Validation results showed varying accuracy levels ranging from the best performing soil pH (CCC = 0.900) to more poorly predictable extractable phosphorus (CCC = 0.654) and sulphur (CCC = 0.708) and depth to bedrock. Sentinel-2 bands SWIR (B11, B12), NIR (B09, B8A), Landsat SWIR bands, and vertical depth derived from 30 m resolution DTM, were the overall most important 30 m resolution covariates. Climatic data images—SM2RAIN, bioclimatic variables and MODIS Land Surface Temperature—however, remained as the overall most important variables for predicting soil chemical variables at continental scale. This publicly available 30-m Soil Information System of Africa aims at supporting numerous applications, including soil and fertilizer policies and investments, agronomic advice to close yield gaps, environmental programs, or targeting of nutrition interventions.

The importance of organic aerosol particles in the environment has been long established, influencing cloud formation and lifetime, absorbing and scattering sunlight, affecting atmospheric composition and impacting on human health. Conventionally, ambient organic particles were considered to exist as liquids. Recent observations in field measurements and studies in the laboratory suggest that they may instead exist as highly viscous semi-solids or amorphous glassy solids under certain conditions, with important implications for atmospheric chemistry, climate and air quality. This review explores our understanding of aerosol particle phase, particularly as identified by measurements of the viscosity of organic particles, and the atmospheric implications of phase state. The phase state of organic particles in the atmosphere has important consequences for the impact of aerosols on climate, visibility, air quality and health. Here, the authors review the evidence for the formation of amorphous glassy particles and the methods for determining aerosol particle viscosity.

Tirzepatide (LY3298176) is a dual GIP and GLP-1 receptor agonist under development for the treatment of type 2 diabetes mellitus (T2DM), obesity, and nonalcoholic steatohepatitis. Early phase trials in T2DM indicate that tirzepatide improves clinical outcomes beyond those achieved by a selective GLP-1 receptor agonist. Therefore, we hypothesized that the integrated potency and signaling properties of tirzepatide provide a unique pharmacological profile tailored for improving broad metabolic control. Here, we establish methodology for calculating occupancy of each receptor for clinically efficacious doses of the drug. This analysis reveals a greater degree of engagement of tirzepatide for the GIP receptor than the GLP-1 receptor, corroborating an imbalanced mechanism of action. Pharmacologically, signaling studies demonstrate that tirzepatide mimics the actions of native GIP at the GIP receptor but shows bias at the GLP-1 receptor to favor cAMP generation over β-arrestin recruitment, coincident with a weaker ability to drive GLP-1 receptor internalization compared with GLP-1. Experiments in primary islets reveal β-arrestin1 limits the insulin response to GLP-1, but not GIP or tirzepatide, suggesting that the biased agonism of tirzepatide enhances insulin secretion. Imbalance toward GIP receptor, combined with distinct signaling properties at the GLP-1 receptor, together may account for the promising efficacy of this investigational agent.

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by the progressive accumulation of amyloid-beta and neurofibrillary tangles of tau in the neocortex. We profiled DNA methylation in two regions of the cortex from 631 donors, performing an epigenome-wide association study of multiple measures of AD neuropathology. We meta-analyzed our results with those from previous studies of DNA methylation in AD cortex (total n  = 2013 donors), identifying 334 cortical differentially methylated positions (DMPs) associated with AD pathology including methylomic variation at loci not previously implicated in dementia. We subsequently profiled DNA methylation in NeuN+ (neuronal-enriched), SOX10+ (oligodendrocyte-enriched) and NeuN–/SOX10– (microglia- and astrocyte-enriched) nuclei, finding that the majority of DMPs identified in ‘bulk’ cortex tissue reflect DNA methylation differences occurring in non-neuronal cells. Our study highlights the power of utilizing multiple measures of neuropathology to identify epigenetic signatures of AD and the importance of characterizing disease-associated variation in purified cell-types. Here the authors identify differences in cortical DNA methylation associated with Alzheimer’s disease pathology, and profiling nuclei from specific cell-types, find that most of these differences reflect variation occurring in non-neuronal cells.