tbuckley/cabot-search huggingface dataset:
Primary cam morphology; bump, burden or bog-standard? A concept analysis
Authors: H Paul Dijkstra, Clare L Ardern, Andreas Serner, Andrea Britt Mosler, Adam Weir, Nia Wyn Roberts, Sean Mc Auliffe, Jason L Oke, Karim M Khan, Mike Clarke, Siôn Glyn-Jones
Journal: British Journal of Sports Medicine (2021)

Cam morphology, a distinct bony morphology of the hip, is prevalent in many athletes, and a risk factor for hip-related pain and osteoarthritis. Secondary cam morphology, due to existing or previous hip disease (eg, Legg-Calve-Perthes disease), is well-described. Cam morphology not clearly associated with a disease is a challenging concept for clinicians, scientists and patients. We propose this morphology, which likely develops during skeletal maturation as a physiological response to load, should be referred to as primary cam morphology. The aim of this study was to introduce and clarify the concept of primary cam morphology.We conducted a concept analysis of primary cam morphology using articles that reported risk factors associated with primary cam morphology; we excluded articles on secondary cam morphology. The concept analysis method is a rigorous eight-step process designed to clarify complex 'concepts'; the end product is a precise definition that supports the theoretical basis of the chosen concept.We propose five defining attributes of primary cam morphology-tissue type, size, site, shape and ownership-in a new conceptual and operational definition. Primary cam morphology is a cartilage or bony prominence (bump) of varying size at the femoral head-neck junction, which changes the shape of the femoral head from spherical to aspherical. It often occurs in asymptomatic male athletes in both hips. The cartilage or bone alpha angle (calculated from radiographs, CT or MRI) is the most common method to measure cam morphology. We found inconsistent reporting of primary cam morphology taxonomy, terminology, and how the morphology is operationalised.We introduce and clarify primary cam morphology, and propose a new conceptual and operational definition. Several elements of the concept of primary cam morphology remain unclear and contested. Experts need to agree on the new taxonomy, terminology and definition that better reflect the primary cam morphology landscape-a bog-standard bump in most athletic hips, and a possible hip disease burden in a selected few.
Effect of different bile acids on the intestine through enterohepatic circulation based on FXR
Authors: Junwei Xiang, Zhengyan Zhang, Hongyi Xie, Chengcheng Zhang, Yan Bai, Hua Cao, Qishi Che, Jiao Guo, Zhengquan Su
Journal: Gut Microbes (2021)

Farnesoid X receptor (FXR) is a nuclear receptor for bile acids (BAs) that is widely expressed in the intestine, liver and kidney. FXR has important regulatory impacts on a wide variety of metabolic pathways (such as glucose, lipid, and sterol metabolism) and has been recognized to ameliorate obesity, liver damage, cholestasis and chronic inflammatory diseases. The types of BAs are complex and diverse. BAs link the intestine with the liver through the enterohepatic circulation. BAs derivatives have entered clinical trials for liver disease. In addition to the liver, the intestine is also targeted by BAs. This article reviews the effects of different BAs on the intestinal tract through the enterohepatic circulation from the perspective of FXR, aiming to elucidate the effects of different BAs on the intestinal tract and lay a foundation for new treatment methods.
Patient Phenotypes and SGLT-2 Inhibition in Type 2 Diabetes
Authors: Abhinav Sharma, Anne Pernille Ofstad, Tariq Ahmad, Bernard Zinman, Isabella Zwiener, David Fitchett, Christoph Wanner, Jyothis T. George, Stefan Hantel, Nihar Desai, Robert J. Mentz
Journal: JACC Heart Failure (2021)

Using latent class analysis (LCA) of EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), this study identified distinct phenotypes in subjects with type 2 diabetes (T2D) and cardiovascular (CV) disease and explored treatment effects across phenotypes.In the EMPA-REG OUTCOME trial, empagliflozin reduced risk of CV death or hospitalization for heart failure (HHF) by 34% in subjects with T2D and CV disease. Among such subjects, there has been limited evaluation of clinical phenotypes.Overall, 7,020 participants were treated with empagliflozin 25 mg, 10 mg, or placebo. For this post hoc analysis, participants were randomly separated into training (two-thirds of patients) and validation (remaining one-third) sets. LCA identified 3 phenotype groups (n = 6,639 with complete data). The phenotype association with CV death or HHF and empagliflozin treatment effect across groups was explored by Cox regression (in training and validation sets).In the training set, phenotype group 1 (n = 1,463; 33.1%) included younger patients with shorter T2D duration and the highest estimated glomerular filtration rate (eGFR). Phenotype group 2 (n = 1,172; 26.5%) included more women with non-coronary artery disease. Phenotype group 3 (n = 1,785; 40.4%) included older patients with advanced coronary disease and the lowest eGFR. The risk of CV death varied across phenotypes (group 2 vs. 1: hazard ratio [HR]; 1.83; 95% confidence interval [CI]: 1.23 to 2.71; group 3 vs. 1: HR: 1.86; 95% CI: 1.30 to 2.67) with similar patterns for CV death or HHF. Consistent treatment effects of empagliflozin were seen across phenotypes in the training and validation sets (interaction p > 0.30).Among participants with T2D, this study identified 3 phenotypes with varying CV risk. The treatment effect across phenotypes reaffirms the robustness of CV death or HHF reduction with empagliflozin. (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients [EMPA-REG OUTCOME]; NCT01131676).
Revealing the importance of carrier-cargo association in delivery of insulin and lipidated insulin
Authors: Ragna Guldsmed Diedrichsen, Stine Harloff-Helleberg, Ulrich Werner, Melissa Besenius, Ekkehard Leberer, Mie Kristensen, Hanne Mørck Nielsen
Journal: Journal of Controlled Release (2021)

Delivery of therapeutic peptides upon oral administration is highly desired and investigations report that the cell-penetrating peptide (CPP) penetratin and its analogues shuffle and penetramax show potential as carriers to enhance insulin delivery. Exploring this, the specific aim of the present study was to understand the impact that their complexation with a lipidated or non-lipidated therapeutic cargo would have on the delivery, to evaluate the effect of differences in membrane interactions in vitro and in vivo, as well as to deduce the mode of action leading to enhanced delivery. Fundamental biophysical aspects were studied by a range of orthogonal methods. Transepithelial permeation of therapeutic peptide was evaluated using the Caco-2 cell culture model supplemented with epithelial integrity measurements, real-time assessment of the carrier peptide effects on cell viability and on mode of action. Pharmacokinetic and pharmacodynamic (PK/PD) parameters were evaluated following intestinal administration to rats and tissue effects were investigated by histology. The biophysical studies revealed complexation of insulin with shuffle and penetramax, but not with penetratin. This corresponded to enhanced transepithelial permeation of insulin, but not of lipidated insulin, when in physical mixture with shuffle or penetramax. The addition of shuffle and penetramax was associated with a lowering of Caco-2 cell monolayer integrity and viability, where the lowering of cell viability was immediate, but reversible. Insulin delivery in rats was enhanced by shuffle and penetramax and accompanied by a 10-20-fold decrease in blood glucose with immediate effect on the intestinal mucosa. In conclusion, shuffle and penetramax, but not penetratin, demonstrated to be potential candidates as carriers for transmucosal delivery of insulin upon oral administration, and their effect depended on association with both cargo and cell membrane. Interestingly, the present study provides novel mechanistic insight that peptide carrier-induced cargo permeation points towards enhancement via the paracellular route in the tight epithelium. This is different from the anticipated belief being that it is the cell-penetrating capability that facilitate transepithelial cargo permeation via a transcellular route.
Differences in cerebral oxygenation during exercise in patients with idiopathic pulmonary fibrosis with and without exertional hypoxemia: does exercise intensity matter?
Authors: K. Dipla, A.K. Boutou, A. Markopoulou, S. Papadopoulos, S. Kritikou, G. Pitsiou, I. Stanopoulos, I. Kioumis, A. Zafeiridis
Journal: Pulmonology (2021)

Patients with idiopathic pulmonary fibrosis (IPF) present respiratory derangements at rest and during exercise, accompanied by exercise intolerance. Some patients may develop profound exertional desaturation even without resting hypoxemia. Evidence suggests the involvement of reduced cerebral-oxygenation in exercise intolerance. We aimed to examine (i) differences in cerebral-oxygenation during exercise between IPF patients with and without isolated exertional desaturation, (ii) whether the impairments in cerebral-oxygenation are detected at similar exercise intensity, and (iii) correlations between cerebral-oxygenation indices, disease severity, and 6-min walk test (6MWT). Patients with IPF (n = 24; 62.1 ± 9.3 years) without resting hypoxemia underwent cardiopulmonary exercise testing (CPET) with cerebral-oxygenation monitoring via near-infrared-spectroscopy (NIRS). Βased on their pulse-oxymetry saturation (SpO2) during CPET, patients were divided into the "exertional-desaturators" group (SpO2nadir≤89% and ≥6% drop in SpO2) and the "non-exertional-desaturators" group (SpO2nadir≥90% and ≤5% drop). During CPET, the "exertional-desaturators" group exhibited lower oxygenated-hemoglobin (-0.67 ± 1.48 vs. 0.69 ± 1.75 μmol/l; p < 0.05) and higher deoxygenated-hemoglobin (1.67 ± 1.13 vs. 0.17 ± 0.62 μmol/l; p < 0.001) than the "non-exertional-desaturators" group. A different pattern (p < 0.01) in cerebral-oxygenation responses was observed in the two groups. In exertional-desaturators oxygenated-hemoglobin declined below baseline even at low/moderate-intensity exercise (p < 0.05), whereas, in non-exertional-desaturators cerebral-oxygenation declined (p < 0.05) at high-intensity exercise. Cerebral-NIRS indices correlated (p < 0.05) with CPET-duration, dyspnea, diffusion capacity, and 6MWT. During incremental exercise, patients with IPF and exertional desaturation present a significant decline in cerebral-oxygenation even during low-intensity exercise. Our findings support the implementation of longer-duration rehabilitation programs in IPF so that lower intensity exercise can be applied at the initial stages. (NCT 03683082)
Orthogonal targeting of osteoclasts and myeloma cells for radionuclide stimulated dynamic therapy induces multidimensional cell death pathways
Authors: Alexander Zheleznyak, Matthew Mixdorf, Lynne Marsala, Julie Prior, Xiaoxia Yang, Grace Cui, Baogang Xu, Steven Fletcher, Francesca Fontana, Gregory Lanza, Samuel Achilefu
Journal: Theranostics (2021)

Rationale: Multiple myeloma (MM) is a multifocal malignancy of bone marrow plasma cells, characterized by vicious cycles of remission and relapse that eventually culminate in death.The disease remains mostly incurable largely due to the complex interactions between the bone microenvironment (BME) and MM cells (MMC).In the "vicious cycle" of bone disease, abnormal activation of osteoclasts (OCs) by MMC causes severe osteolysis, promotes immune evasion, and stimulates the growth of MMC.Disrupting these cancer-stroma interactions would enhance treatment response.Methods: To disrupt this cycle, we orthogonally targeted nanomicelles (NM) loaded with non-therapeutic doses of a photosensitizer, titanocene (TC), to VLA-4 (α4ß1, CD49d/CD29) expressing MMC (MM1.S) and αvß3 (CD51/CD61) expressing OC.Concurrently, a non-lethal dose of a radiopharmaceutical, 18 F-fluorodeoxyglucose ([ 18 F]FDG) administered systemically interacted with TC (radionuclide stimulated therapy, RaST) to generate cytotoxic reactive oxygen species (ROS).The in vitro and in vivo effects of RaST were characterized in MM1.S cell line, as well as in xenograft and isograft MM animal models.Results: Our data revealed that RaST induced non-enzymatic hydroperoxidation of cellular lipids culminating in mitochondrial dysfunction, DNA fragmentation, and caspase-dependent apoptosis of MMC using VLA-4 avid TC-NMs.RaST upregulated the expression of BAX, Bcl-2, and p53, highlighting the induction of apoptosis via the BAK-independent pathway.The enhancement of multicopper oxidase enzyme F5 expression, which inhibits lipid hydroperoxidation and Fenton reaction, was not sufficient to overcome RaST-induced increase in the accumulation of irreversible function-perturbing α,ß-aldehydes that exerted significant and long-lasting damage to both DNA and proteins.In vivo, either VLA-4-TC-NM or αvß3-TC-NMs RaST induced a significant therapeutic effect on immunocompromised but not immunocompetent MM-bearing mouse models.Combined treatment with both VLA-4-TC-NM and αvß3-TC-NMs synergistically inhibited osteolysis, reduced tumor burden, and prevented rapid relapse in both in vivo models of MM.Conclusions: By targeting MM and bone cells simultaneously, combination RaST suppressed MM disease progression through a multi-prong action on the vicious cycle of bone cancer.Instead of using the standard multidrug approach, our work reveals a unique photophysical treatment paradigm that uses nontoxic doses of a single light-sensitive drug directed orthogonally to cancer and bone cells, followed by radionuclide-stimulated generation of ROS to inhibit tumor progression and minimize osteolysis in both immunocompetent murine and immunocompromised human MM models.
Toward a complete cure for chronic hepatitis B: Novel therapeutic targets for hepatitis B virus
Authors: Sun Woong Kim, Jun Sik Yoon, Minjong Lee, Yuri Cho
Journal: Clinical and Molecular Hepatology (2021)

Hepatitis B virus (HBV) affects approximately 250 million patients worldwide, resulting in the progression to cirrhosis and hepatocellular carcinoma, which are serious public health problems. Although universal vaccination programs exist, they are only prophylactic and not curative. In the HBV life cycle, HBV forms covalently closed circular DNA (cccDNA), which is the viral minichromosome, in the nuclei of human hepatocytes and makes it difficult to achieve a complete cure with the current nucleos(t)ide analogs and interferon therapies. Current antiviral therapies rarely eliminate cccDNA; therefore, lifelong antiviral treatment is necessary. Recent trials for antiviral treatment of chronic hepatitis B have been focused on establishing a functional cure, defined by either the loss of hepatitis B surface antigen, undetectable serum HBV DNA levels, and/or seroconversion to hepatitis B surface antibody. Novel therapeutic targets and molecules are in the pipeline for early clinical trials aiming to cure HBV infection. The ideal strategy for achieving a long-lasting functional or complete cure might be using combination therapies targeting different steps of the HBV life cycle and immunomodulators. This review summarizes the current knowledge about novel treatments and combination treatments for a complete HBV cure.
David Oliver: Could separating NHS “hot” and “cold” inpatient sites work?
Authors: David Oliver
Journal: BMJ (2021)

Is it realistic to think of separating NHS hospital sites more effectively for “cold” (elective) and “hot” (acute and urgent) care, so that outbreaks or seasonal surges don’t lead to elective care being cancelled or delayed? This month over five million people were waiting for planned surgery, procedures, tests, and outpatient appointments in England—the highest figure on record.1 The Times reported that “NHS chiefs are braced for nine million patients on waiting lists by the end of the year while Sajid Javid, the health secretary, has warned that it could go as high as 13 million.”2

After previous successful drives by government and NHS leaders to tackle waiting lists, waiting times for planned (elective) care had been deteriorating in the years before the pandemic because of workforce pressures, financial constraints, and insufficient beds, clinics, investigation suites, or diagnostic services such as imaging.3 The pandemic massively accelerated worsening …
A Phase I Dose-Escalation and Expansion Study of Telaglenastat in Patients with Advanced or Metastatic Solid Tumors
Authors: James J. Harding, Melinda Telli, Pamela Munster, Martin H. Voss, Jeffrey R. Infante, Angela DeMichele, Mark Dunphy, Mai H. Le, Chris Molineaux, Keith Orford, Frank Parlati, Sam H. Whiting, Mark K. Bennett, Nizar M. Tannir, Funda Meric-Bernstam
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Glutamine is a critical fuel for solid tumors. Interference with glutamine metabolism is deleterious to neoplasia in preclinical models. A phase I study of the oral, first-in-class, glutaminase (GLS) inhibitor telaglenastat was conducted in treatment-refractory solid tumor patients to define recommended phase II dose (RP2D) and evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity. Patients and Methods: Dose escalation by 3 + 3 design was followed by exploratory tumor-/biomarker-specific cohorts. Results: Among 120 patients, fatigue (23%) and nausea (19%) were the most common toxicity. Maximum tolerated dose was not reached. Correlative analysis indicated &amp;gt;90% GLS inhibition in platelets at plasma exposures &amp;gt;300 nmol/L, &amp;gt;75% tumoral GLS inhibition, and significant increase in circulating glutamine. RP2D was defined at 800 mg twice-daily. Disease control rate (DCR) was 43% across expansion cohorts (overall response rate 5%, DCR 50% in renal cell carcinoma). Conclusions: Telaglenastat is safe, with a favorable PK/PD profile and signal of antitumor activity, supporting further clinical development.
Association of Cycling With All-Cause and Cardiovascular Disease Mortality Among Persons With Diabetes
Authors: Mathias Ried-Larsen, Martin Gillies Rasmussen, Kim Blond, Thure F. Overvad, Kim Overvad, Karen Steindorf, Verena Katzke, Julie L. M. Andersen, Kristina E. N. Petersen, Dagfinn Aune, Kostas K. Tsilidis, Alicia K. Heath, Keren Papier, Salvatore Panico, Giovanna Masala, Valeria Pala, Elisabete Weiderpass, Heinz Freisling, Manuela M. Bergmann, W. M. Monique Verschuren, Raul Zamora-Ros, Sandra M. Colorado-Yohar, Annemieke M. W. Spijkerman, Matthias B. Schulze, Eva M. A. Ardanaz, Lars Bo Andersen, Nick Wareham, Søren Brage, Anders Grøntved
Journal: JAMA Internal Medicine (2021)

Premature death from all causes and cardiovascular disease (CVD) causes is higher among persons with diabetes.
Improved Survival Outcomes By Iron Chelating Therapy with Deferasirox after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia
Authors: Byung Sik Cho, Young-Woo Jeon, Sung-Soo Park, Jae-Ho Yoon, Sung-Eun Lee, Ki-Seong Eom, Yoo-Jin Kim, Seok Lee, Chang-Ki Min, Seok-Goo Cho, Dong-Wook Kim, Jong-Wook Lee, Woo-Sung Min, Heeje Kim
Journal: Blood (2017)
Microglia in Alzheimer's disease at single-cell level. Are there common patterns in humans and mice?
Authors: Yun Chen, Marco Colonna
Journal: The Journal of Experimental Medicine (2021)

Alzheimer's disease (AD) is characterized by extracellular aggregates of amyloid β peptides, intraneuronal tau aggregates, and neuronal death. This pathology triggers activation of microglia. Because variants of genes expressed in microglia correlate with AD risk, microglial response to pathology plausibly impacts disease course. In mouse AD models, single-cell RNA sequencing (scRNA-seq) analyses delineated this response as progressive conversion of homeostatic microglia into disease-associated microglia (DAM); additional reactive microglial populations have been reported in other models of neurodegeneration and neuroinflammation. We review all of these microglial signatures, highlighting four fundamental patterns: DAM, IFN-microglia, MHC-II microglia, and proliferating microglia. We propose that all reported microglia populations are either just one or a combination, depending on the clustering strategy applied and the disease model. We further review single-nucleus RNA sequencing (snRNA-seq) data from human AD specimens and discuss reasons for parallels and discrepancies between human and mouse transcriptional profiles. Finally, we outline future directions for delineating the microglial impact in AD pathogenesis.
Platelet EVs contain an active proteasome involved in protein processing for antigen presentation via MHC-I molecules
Authors: Genevieve Marcoux, Audrée Laroche, Stephan Hasse, Marie Bellio, Maroua Mbarik, Marie Tamagne, Isabelle Allaeys, Anne Zufferey, Tania Lévesque, Johan Rebetz, Annie Karakeussian-Rimbaud, Julie Turgeon, Sylvain G. Bourgoin, Hind Hamzeh-Cognasse, Fabrice Cognasse, Rick Kapur, John W. Semple, Marie-Josée Hébert, France Pirenne, Herman S. Overkleeft, Bogdan I. Florea, Mélanie Dieude, Benoît Vingert, Eric Boilard
Journal: Blood (2021)
Abstract 17835: Effect of Cardiopulmonary Resuscitation Training on Favorable Neurological Outcome for In-Hospital Cardiac Arrest
Authors: Kei Yoshikawa, Hiroyuki Yokoyama, Naohiro Yonemoto, Hiroshi Nonogi
Journal: Circulation (2011)

Background: Many training courses for CPR have been performed to medical personnel but few data have been reported those effect. Method: From 2008 to 2009, during 24 month, 491 patients were registered in the Japanese Registry of CPR for In-hospital Cardiac Arrest (J-RCPR). In this study, 445 patients treated by the first responder received the CPR training (Group T n=357) and non-trained first responder (group n-T n=88) were analyzed. We evaluated the ratio of return of spontaneous circulation (ROSC) and good neurological function at discharge (CPC1 or 2 in Glasgow-Pittsburgh cerebral performance category) in each groups. We also analyzed each indexes by initial rhythm was VF/VT arrest (n=122) and PEA/Asystole (n=316). Result: The ratio of ROSC, good neurological performance were 65.8%, 21.1% in group T, and 59.1,10.3% in group n-T (In good CPC p&lt;0.05). In VF/VT, the ratio were 80.2%, 45.5% in group T, and 74.2%,15.4% in group n-T (In good CPC p&lt;0.01). In PEA/Asystole, the ratio were 60.8%, 12.5% in group T, and 50.0%, 5.9% in group n-T. Conclusion: In-hospital cardiac arrest treated by the first responder with the CPR training is significantly associated with higher rate of favorable neurological outcome, especially in VF/VT
Addressing Social Adversity to Improve Outcomes for Children After Liver Transplant
Authors: Sharad I. Wadhwani, Laura Gottlieb, John C. Bucuvalas, Courtney Lyles, Jennifer C. Lai
Journal: Hepatology (2021)

The social determinants of health, defined as the conditions in which we live, learn, work, and play, undoubtedly impact health outcomes. Social adversity in childhood perpetuates over the life course and has consequences extending into adulthood. This link between social adversity and adverse outcomes extends to children undergoing liver transplant, with children from socioeconomically deprived neighborhoods experiencing a greater burden of morbidity and mortality after transplant. Yet, we lack an in-depth understanding of how to address social adversity for these children. Herein, we lay out a strategy to develop and test interventions to address social adversity for children undergoing liver transplant. To do so, we believe that more granular data on how specific social risk factors (e.g., food insecurity) impact outcomes for children after liver transplant are needed. This will provide the liver transplant community with knowledge on the most pressing problems. Then, using the National Academies of Sciences, Engineering, and Medicine's framework for integrating social needs into medical care, the health system can start to develop and test health system interventions. We believe that attending to our patients' social adversity will realize improved outcomes for children undergoing liver transplant.