Femoroacetabular impingement is a recognized source of hip pain and cause of labral and articular cartilage injury. Persistent femoroacetabular impingement has been recognized as a source of inferior ...patient-reported outcomes, and attempts to define a “normal” α-angle has resulted in more aggressive resection of cam lesions. An overzealous femoroplasty may result in iatrogenic hip instability. A dynamic intraoperative examination may be the best way to truly recognize this problem, in particular, by visualizing the loss of the suction seal, as the cam resection engages the acetabulum, resulting in subluxation. A soft tissue “remplissage” salvage procedure may offer an option to correct cam overresection and improve patient outcomes during revision arthroscopy, as we continue to search for the “right” amount of cam correction to perform.
Short lipidated peptide sequences derived from various intracellular loop regions of G protein-coupled receptors (GPCRs) are named pepducins and act as allosteric modulators of a number of GPCRs. ...Recently, a pepducin selectively targeting the C-X-C chemokine receptor type 4 (CXCR4) was found to be an allosteric agonist, active in both cell-based assays and in vivo. However, the precise mechanism of action of this class of ligands remains poorly understood. In particular, given the diversity of signaling effectors that can be engaged by a given receptor, it is not clear whether pepducins can show biased signaling leading to functional selectivity. To explore the ligand-biased potential of pepducins, we assessed the effect of the CXCR4 selective pepducin, ATI-2341, on the ability of the receptor to engage the inhibitory G proteins (Gi1, Gi2 and Gi3), G13, and β-arrestins. Using bioluminescence resonance energy transfer-based biosensors, we found that, in contrast to the natural CXCR4 ligand, stromal cell-derived factor-1α, which promotes the engagement of the three Gi subtypes, G13 and the two β-arrestins, ATI-2341 leads to the engagement of the Gi subtypes but not G13 or the β-arrestins. Calculation of the transduction ratio for each pathway revealed a strong negative bias of ATI-2341 toward G13 and β-arrestins, revealing functional selectivity for the Gi pathways. The negative bias toward β-arrestins results from the reduced ability of the pepducin to promote GPCR kinase-mediated phosphorylation of the receptor. In addition to revealing ligand-biased signaling of pepducins, these findings shed some light on the mechanism of action of a unique class of allosteric regulators.
Out-of-plane lesions pose challenges for CT-guided interventions. Augmented reality (AR) headsets are capable to provide holographic 3D guidance to assist CT-guided targeting. A prospective trial was ...performed assessing CT-guided lesion targeting on an abdominal phantom with and without AR guidance using HoloLens 2. Eight operators performed a cumulative total of 86 needle passes. Total needle redirections, radiation dose, procedure time, and puncture rates of nontargeted lesions were compared with and without AR. Mean number of needle passes to reach the target reduced from 7.4 passes without AR to 3.4 passes with AR (p = 0.011). Mean CT dose index decreased from 28.7 mGy without AR to 16.9 mGy with AR (p = 0.009). Mean procedure time reduced from 8.93 min without AR to 4.42 min with AR (p = 0.027). Puncture rate of a nontargeted lesion decreased from 11.9% without AR (7/59 passes) to 0% with AR (0/27 passes). First needle passes were closer to the ideal target trajectory with AR versus without AR (4.6° vs 8.0° offset, respectively, p = 0.018). AR reduced variability and elevated the performance of all operators to the same level irrespective of prior clinical experience. AR guidance can provide significant improvements in procedural efficiency and radiation dose savings for targeting out-of-plane lesions.
Hip instability continues to be a challenge in hip preservation. Our understanding of the role of osseous anatomy, labral integrity and soft-tissue stabilizers has increased dramatically over the ...past several decades. Connective-tissue disorders such as Ehlers-Danlos syndrome pose a significant challenge to the management of instability in all joints but particularly in the hip. Ligamentum teres tears have been found to be more common than previously thought, although their significance is still not well understood. In patients with both Ehlers-Danlos syndrome and ligamentum teres tears, reconstruction and capsular plication result in moderate success, but not in all cases.
The private higher education (HE) sector in the UK is subject to little oversight or regulation. Consequently, it remains a largely unknown quantity. Yet, the UK government is keen to foster the ...growth of private providers as a means of stimulating competition across the entire HE sector that will purportedly lead to 'a greater choice of more innovative and better quality products and services at lower cost' (DBIS
2016a
, 8). We document the landscape of private higher education provision in the UK to assess whether private providers are likely to be able to perform the role envisaged for them by government. We analyse data for 802 private providers in the UK collected from provider's websites and other publicly available sources in 2017. A latent class analysis indicates that the sector can be broken down into four distinctive types of providers: (1) for-profit providers principally offering business/IT courses at sub-degree level (c.50%) (2) or at bachelors or masters level (c.10%), (3) not-for-profit providers offering other kinds of specialist provision at bachelors and masters level (c.27%), and (4) longer-standing for-profit providers including those with their own degree-awarding powers delivering courses mainly at masters level (c.13%). Three of the four provider types offer little in the way of traditional bachelor degree provision, and the most common provider type is subject to virtually no regulatory oversight and highly vulnerable to 'market exit'. These findings cast doubt on the capacity of private HE providers to replace or enhance publicly funded HE provision.
ATR-101 is a novel, oral drug candidate currently in development for the treatment of adrenocortical cancer. ATR-101 is a selective and potent inhibitor of acyl-coenzyme A:cholesterol ...O-acyltransferase 1 (ACAT1), an enzyme located in the endoplasmic reticulum (ER) membrane that catalyzes esterification of intracellular free cholesterol (FC). We aimed to identify mechanisms by which ATR-101 induces adrenocortical cell death. In H295R human adrenocortical carcinoma cells, ATR-101 decreases the formation of cholesteryl esters and increases FC levels, demonstrating potent inhibition of ACAT1 activity. Caspase-3/7 levels and terminal deoxynucleotidyl transferase 2′-deoxyuridine 5′-triphosphate nick end labeled-positive cells are increased by ATR-101 treatment, indicating activation of apoptosis. Exogenous cholesterol markedly potentiates the activity of ATR-101, suggesting that excess FC that cannot be adequately esterified increases caspase-3/7 activation and subsequent cell death. Inhibition of calcium release from the ER or the subsequent uptake of calcium by mitochondria reverses apoptosis induced by ATR-101. ATR-101 also activates multiple components of the unfolded protein response, an indicator of ER stress. Targeted knockdown of ACAT1 in an adrenocortical cell line mimicked the effects of ATR-101, suggesting that ACAT1 mediates the cytotoxic effects of ATR-101. Finally, in vivo treatment of dogs with ATR-101 decreased adrenocortical steroid production and induced cellular apoptosis that was restricted to the adrenal cortex. Together, these studies demonstrate that inhibition of ACAT1 by ATR-101 increases FC, resulting in dysregulation of ER calcium stores that result in ER stress, the unfolded protein response, and ultimately apoptosis.
The sudden closure of higher education providers is virtually unknown among publicly funded higher education institutions in the UK, but “market exit” is commonplace among private higher education ...providers. The UK government is actively championing the expansion of private higher education providers despite a dearth of research on the factors associated with a heightened risk of market exit within this part of the UK higher education sector. We set out to fill this gap in knowledge by utilizing existing data on private higher education providers active in the UK in 2014 supplemented by newly collected data on the status of these providers in 2019. The likelihood of market exit was higher for more recently founded providers, those operating for profit, those specializing in Business or IT or else having no particular specialization, and those located in London—all features that represent areas of greatest competition in the private higher education sector. Further risk factors associated with an increased likelihood of market exit were no external quality assessment, no access to publicly backed tuition fee loans, and the removal of the legal right to recruit international students. This second set of risk factors suggest that it is not just denial of revenue streams that increases the likelihood of market exit but estrangement from an officially regulated higher education system.
Conditions defined by persistent "medically unexplained" physical symptoms and syndromes (MUS) are common and disabling. Veterans from the Gulf War (deployed 1990-1991) have notably high prevalence ...and disability from MUS conditions. Individuals with MUS report that providers do not recognize their MUS conditions. Our goal was to determine if Veterans with MUS receive an ICD-10 diagnosis for a MUS condition or receive disability benefits available to them for these conditions.
A chart review was conducted with US Veterans who met case criteria for Gulf War Illness, a complex MUS condition (N = 204, M = 53 years-old, SD = 7). Three coders independently reviewed Veteran's medical records for MUS condition diagnosis or service-connection along with comorbid mental and physical health conditions. Service-connection refers to US Veterans Affairs disability benefits eligibility for conditions or injuries experienced during or exacerbated by military service.
Twenty-nine percent had a diagnosis of a MUS condition in their medical record, the most common were irritable colon/irritable bowel syndrome (16%) and fibromyalgia (11%). Slightly more Veterans were service-connected for a MUS condition (38%) as compared to diagnosed. There were high rates of diagnoses and service-connection for mental health (diagnoses 76% and service-connection 74%), musculoskeletal (diagnoses 86%, service-connection 79%), and illness-related conditions (diagnoses 98%, service-connection 49%).
Given that all participants were Gulf War Veterans who met criteria for a MUS condition, our results suggest that MUS conditions in Gulf War Veterans are under-recognized with regard to clinical diagnosis and service-connected disability. Veterans were more likely to be diagnosed and service-connected for musculoskeletal-related and mental health conditions than MUS conditions. Providers may need education and training to facilitate diagnosis of and service-connection for MUS conditions. We believe that greater acknowledgement and validation of MUS conditions would increase patient engagement with healthcare as well as provider and patient satisfaction with care.
Chemo-immunotherapy uses combined systemic therapies for resectable and unresectable tumors. This approach is gaining clinical momentum, but survival increases leave considerable room for ...improvement. A novel form of Pulsed Electric Field (PEF) ablation combines focal tissue destruction with immune activation in preclinical settings. The PEFs induce lethal cell damage without requiring thermal processes, leaving cellular proteins intact. This affords PEF a favorable safety profile, improved antigenicity, and significant immunostimulatory damage-associated molecular pattern release compared to other focal therapies. Preclinical investigations demonstrate a combinatorial benefit of PEF with immunostimulation. This study evaluates whether this proprietary PEF therapy induces an immunostimulatory effect sufficient to augment systemic neoadjuvant chemotherapy and immunotherapy to reverse metastatic disease in an immune-cold murine tumor model. To determine whether PEF improves a neoadjuvant chemo-immunotherapy standard-of-care, partial PEF ablation was delivered to orthotopically inoculated 4T1 metastatic tumors in addition to combinations of cisplatin chemotherapy and/or αPD-1 immunotherapy, followed by resection. In addition, to determine whether PEF combined with chemo-immunotherapy improves local and metastatic response in unresectable populations, partial PEF ablation was added to chemo-immunotherapy in mice that did not receive resection. Blood cytokines and flow cytometry evaluated immune response. Partial PEF ablation generates an immunostimulatory tumor microenvironment, increases systemic immune cell populations, slows tumor growth, and prolongs survival relative to neoadjuvant systemic therapies-alone. These data suggest the addition of this proprietary PEF locoregional therapy may synergize with systemic standard-of-care paradigms to improve outcomes with potential or demonstrated metastatic disease in both resectable and unresectable patient cohorts.
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