Successful Crizotinib-targeted Therapy of Pediatric Unresectable ERC1::ALK Fusion Sarcoma.

Anaplastic lymphoma kinase ( ALK )-fusion sarcomas are rare part of the emerging theoretically targetable tyrosine kinase RAS::MAPK pathway fusion myopericytic-ovoid sarcomas. We report our clinicopathologic and treatment experience with an ALK fusion sarcoma. A novel ELKS/RAB6-interacting/CAST family member 1 - unaligned ALK fusion infiltrative nonmetastatic low-grade sarcoma of the right hand of a 15-month-old male was treated with crizotinib, an ALK tyrosine kinase inhibitor as oral monotherapy, inducing complete radiographic and clinical resolution by 10 months and sustained response now over 12 months after elective discontinuation. Crizotinib can successfully be used to treat unresectable novel ALK fusion sarcomas.

The Society for Pediatric Radiology Magnetic Resonance Imaging and Emergency and Trauma Imaging Committees' consensus protocol recommendation for rapid MRI for evaluating suspected appendicitis in children.

The imaging evaluation of acute abdominal pain in children with suspected appendicitis has evolved to include rapid abdominopelvic MRI (rMRI) over recent years. Through a collaborative effort between the Magnetic Resonance Imaging (MRI) and Emergency and Trauma Imaging Committees of the Society for Pediatric Radiology (SPR), we conducted a survey on the utilization of rMRI to assess practice specifics and protocols. Subsequently, we present a proposed consensus rMRI protocol derived from the survey results, literature review, and discussion and consensus between committee members.

The Interplay of Permeability, Metabolism, Transporters, and Dosing in Determining the Dynamics of the Tissue/Plasma Partition Coefficient and Volume of Distribution-A Theoretical Investigation Using Permeability-Limited, Physiologically Based Pharmacokinetic Modeling.

A permeability-limited physiologically based pharmacokinetic (PBPK) model featuring four subcompartments (corresponding to the intracellular and extracellular water of the tissue, the residual plasma, and blood cells) for each tissue has been developed in MATLAB/SimBiology and applied to various what-if scenario simulations. This model allowed us to explore the complex interplay of passive permeability, metabolism in tissue or residual blood, active uptake or efflux transporters, and different dosing routes (intravenous (IV) or oral (PO)) in determining the dynamics of the tissue/plasma partition coefficient (Kp) and volume of distribution (Vd) within a realistic pseudo-steady state. Based on the modeling exercise, the permeability, metabolism, and transporters demonstrated significant effects on the dynamics of the Kp and Vd for IV bolus administration and PO fast absorption, but these effects were not as pronounced for IV infusion or PO slow absorption. Especially for low-permeability compounds, uptake transporters were found to increase both the Kp and Vd at the pseudo-steady state (Vdss), while efflux transporters had the opposite effect of decreasing the Kp and Vdss. For IV bolus administration and PO fast absorption, increasing tissue metabolism was predicted to elevate the Kp and Vdss, which contrasted with the traditional derivation from the steady-state perfusion-limited PBPK model. Moreover, metabolism in the residual blood had more impact on the Kp and Vdss compared to metabolism in tissue. Due to its ability to offer a more realistic description of tissue dynamics, the permeability-limited PBPK model is expected to gain broader acceptance in describing clinical PK and observed Kp and Vdss, even for certain small molecules like cyclosporine, which are currently treated as perfusion-limited in commercial PBPK platforms.

Movement Disorder Specialists Survey Regarding Use of Telemedicine During the COVID-19 Pandemic.

Aim: To assess the overall satisfaction level of movement disorder specialists using a virtual platform during the COVID-19 pandemic. Methods: This was a multicenter cross-sectional survey for a 6-month period during the beginning of the COVID-19 pandemic. Movement disorder specialists, who utilized telehealth visits from March 2020 to August 2020, were included. The study surveys, including provider's satisfaction with the care that they were able to provide and visit quality, were completed by the provider after each visit. Results: A total of 206 visits, provided by movement disorder specialists, were analyzed. Zoom was the most popular platform used for remote visits (70, 34%). A backup platform was not needed in the majority of movement disorder visits (171, 83%). The majority of physicians were very satisfied or satisfied with the care provided (72.9%) and visit quality (61%). Conclusions: The satisfaction level of specialists using telemedicine during COVID-19 was high despite having encounters with elderly patients with cognitive impairment or lacking advanced skills with technology.

Non-Hodgkin Lymphoma Metabolism.

Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of lymphoid neoplasms with different biological characteristics. About 90% of all lymphomas in the United States originate from B lymphocytes, while the remaining originate from T cells [1]. The treatment of NHLs depends on the neoplastic histology and stage of the tumor, which will indicate whether radiotherapy, chemotherapy, or a combination is the best suitable treatment [2]. The American Cancer Society describes the staging of lymphoma as follows: Stage I is lymphoma in a single node or area. Stage II is when that lymphoma has spread to another node or organ tissue. Stage III is when it has spread to lymph nodes on two sides of the diaphragm. Stage IV is when cancer has significantly spread to organs outside the lymph system. Radiation therapy is the traditional therapeutic route for localized follicular and mucosa-associated lymphomas. Chemotherapy is utilized for the treatment of large-cell lymphomas and high-grade lymphomas [2]. However, the treatment of indolent lymphomas remains problematic as the patients often have metastasis, for which no standard approach exists [2].

How do people in prison feel about opt-out hepatitis C virus testing?

The prison population is central to the campaign to eliminate hepatitis C virus as a public health threat. In the UK, this has led to the introduction of a national 'opt-out' policy, requiring people in prison to be tested for HCV unless they decline, with a target to test 75% of those admitted. However, in a representative prison estate in the East Midlands of England (20,000 prison entrants per annum) testing rates were only 13.4%. This qualitative study explains why the rates of test uptake are so far short of target. This qualitative study examines the experiences of 45 people in prison about hepatitis C virus testing in an English category C (low security) prison. The data collection method was semi-structured interviews. The data were coded and analysed according to the research questions, and interpretation of the data was aided by the use of a thematic network approach. The themes Fear, Insufficient Knowledge, Stigma, Privacy, Choice and Prison Life emerged as the principal barriers to test uptake. Test Uptake Facilitators that promoted testing were identified by participants and benefits presented of prison health care being a Health Farm. In order to increase hepatitis C virus test uptake, significant changes and flexibility in the timing, location, and staff deployed to test are required. Providing information to people in prison about hepatitis C virus transmission and treatment may reduce fears and enable the test uptake target to be met and sustained.

The anatomy and physiology of the terminal thoracic duct and ostial valve in health and disease: potential implications for intervention.

The thoracic duct (TD) transports lymph drained from the body to the venous system in the neck via the lymphovenous junction. There has been increased interest in the TD lymph (including gut lymph) because of its putative role in the promotion of systemic inflammation and organ dysfunction during acute and critical illness. Minimally invasive TD cannulation has recently been described as a potential method to access TD lymph for investigation. However, marked anatomical variability exists in the terminal segment and the physiology regarding the ostial valve and terminal TD is poorly understood. A systematic review was conducted using three databases from 1909 until May 2017. Human and animal studies were included and data from surgical, radiological and cadaveric studies were retrieved. Sixty-three articles from the last 108 years were included in the analysis. The terminal TD exists as a single duct in its terminal course in 72% of cases and 13% have multiple terminations: double (8.5%), triple (1.8%) and quadruple (2.2%). The ostial valve functions to regulate flow in relation to the respiratory cycle. The patency of this valve found at the lymphovenous junction opening, is determined by venous wall tension. During inspiration, central venous pressure (CVP) falls and the valve cusps collapse to allow antegrade flow of lymph into the vein. During early expiration when CVP and venous wall tension rises, the ostial valve leaflets cover the opening of the lymphovenous junction preventing antegrade lymph flow. During chronic disease states associated with an elevated mean CVP (e.g. in heart failure or cirrhosis), there is a limitation of flow across the lymphovenous junction. Although lymph production is increased in both heart failure and cirrhosis, TD lymph outflow across the lymphovenous junction is unable to compensate for this increase. In conclusion the terminal TD shows marked anatomical variability and TD lymph flow is controlled at the ostial valve, which responds to changes in CVP. This information is relevant to techniques for cannulating the TD, with the aid of minimally invasive methods and high resolution ultrasonography, to enable longitudinal physiology and lymph composition studies in awake patients with both acute and chronic disease.

The Primary Physis.

The primary physis is responsible for long bone growth in children and adolescents. Injury and physiologic or metabolic stress to the primary physis present unique radiologic findings that are important for radiologists to recognize and diagnose. Appreciation of the anatomy and histology of the primary physis forms the basis for understanding the imaging findings associated with pathologic conditions affecting the primary physis. Salter-Harris injuries, physeal bars, growth arrest lines, rickets, and focal periphyseal edema zones are common conditions with recognizable radiologic presentations. Proper diagnosis of these primary physeal conditions will aid in the treatment of affected pediatric patients.

Non-Hodgkin Lymphoma Metabolism.

KEY POINTS: Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of lymphoid neoplasms with differing biological characteristics. About 90% of all lymphomas in the United States originate from B lymphocytes, while the remaining originate from T cells [1]. The treatment of NHLs depends on neoplastic histology and the stage of the tumor, which will indicate whether radiotherapy, chemotherapy, or a combination is the best suitable treatment [2]. The American Cancer Society describes the staging of lymphoma as follows: Stage I is lymphoma in a single node or area. Stage II is when that lymphoma has spread to another node or organ tissue. Stage III is when it has spread to lymph nodes in two sides of the diaphragm. Stage IV is when the cancer has significantly spread to organs outside the lymph system. Radiation therapy is the traditional therapeutic route for localized follicular and mucosa-associated lymphomas. Chemotherapy is utilized for the treatment of large cell lymphomas and high-grade lymphomas [2]. However, treatment of indolent lymphomas remains problematic as the patients often have metastasis for which no standard approach exists [2].

Animal maltreatment law: Evolving efforts to protect animals and their forensic mental health implications.

Animals have long formed an important part of human communities and served various roles in human activities. Some of the earliest human civilizations developed laws that protected animals for assorted reasons, including their economic value, religious beliefs pertaining to animals, and societal concerns about cleanliness. In the 1800s, Western thinkers began to view animals as having rights of their own and proposed legislation that changed the legal landscape regarding animal maltreatment. In the United States today there are widely varying laws designed to address the various forms of animal maltreatment. Each state's laws are different. Some states have modern statutes designed to identify and punish animal maltreatment, and others are relatively lax in their consideration of what constitutes abuse. The purpose of this article is to review the development of animal maltreatment legislation from ancient civilization to the present day in the United States; to identify current legislative reforms designed to assist in investigating and prosecuting animal abusers; to describe the role that forensic mental health experts may play in evaluating abusers for a variety of related concerns, including violence risk, sexual violence risk, and fitness for guardianship of an animal; and to delineate areas requiring further research to improve the forensic evaluation of animal abusers.

A review on laser and light-based therapies for alopecia areata.

Alopecia areata is a form of non-scarring alopecia that results from a hyperactive immune response of T cells against hair follicles. Many patients with visible hair loss experience psychological and emotional distress, as a result of their cosmetic disfigurement, and frequently seek treatment. However, existing treatment methods, such as corticosteroids, topical irritants, sensitizing agents, immunosuppressants, and psoralen plus ultraviolet light A, may result in various adverse effects and often lack efficacy. Laser and light treatments offer a safe and effective alternative. This review aims to provide clinicians with a comprehensive summary of laser and light-based modalities used for the treatment of alopecia areata. Currently, the excimer laser is the most widely studied device and has shown positive results thus far. However, the development of future randomized controlled clinical trials will help determine the appropriate treatment protocols necessary, in order to achieve superior clinical outcomes.

Overactive cannabinoid 1 receptor in podocytes drives type 2 diabetic nephropathy.

Diabetic nephropathy is a major cause of end-stage kidney disease, and overactivity of the endocannabinoid/cannabinoid 1 receptor (CB1R) system contributes to diabetes and its complications. Zucker diabetic fatty (ZDF) rats develop type 2 diabetic nephropathy with albuminuria, reduced glomerular filtration, activation of the renin-angiotensin system (RAS), oxidative/nitrative stress, podocyte loss, and increased CB1R expression in glomeruli. Peripheral CB1R blockade initiated in the prediabetic stage prevented these changes or reversed them when animals with fully developed diabetic nephropathy were treated. Treatment of diabetic ZDF rats with losartan, an angiotensin II receptor-1 (Agtr1) antagonist, attenuated the development of nephropathy and down-regulated renal cortical CB1R expression, without affecting the marked hyperglycemia. In cultured human podocytes, CB1R and desmin gene expression were increased and podocin and nephrin content were decreased by either the CB1R agonist arachydonoyl-2'-chloroethylamide, angiotensin II, or high glucose, and the effects of all three were antagonized by CB1R blockade or siRNA-mediated knockdown of CNR1 (the cannabinoid type 1 receptor gene). We conclude that increased CB1R signaling in podocytes contributes to the development of diabetic nephropathy and represents a common pathway through which both hyperglycemia and increased RAS activity exert their deleterious effects, highlighting the therapeutic potential of peripheral CB1R blockade.

Insights into zinc and cadmium biology in the nematode Caenorhabditis elegans.

Zinc is an essential metal that is involved in a wide range of biological processes, and aberrant zinc homeostasis is implicated in multiple human diseases. Cadmium is chemically similar to zinc, but it is a nonessential environmental pollutant. Because zinc deficiency and excess are deleterious, animals require homeostatic mechanisms to maintain zinc levels in response to dietary fluctuations. The nematode Caenorhabditis elegans is emerging as a powerful model system to investigate zinc trafficking and homeostasis as well as cadmium toxicity. Here we review genetic and molecular studies that have combined to generate a picture of zinc homeostasis based on the transcriptional control of zinc transporters in intestinal cells. Furthermore, we summarize studies of cadmium toxicity that reveal intriguing parallels with zinc biology.

Indications, techniques, and clinical outcomes of thoracic duct interventions in patients: a forgotten literature?

BACKGROUND: The evolution of the "gut-lymph concept" has promoted thoracic duct (TD) lymph drainage as a possible treatment to reduce systemic inflammation and end-organ dysfunction in acute illness. The aim was to review the published experience of thoracic duct interventions (TDIs) aimed at improving clinical outcomes. METHODS: A search of three databases (MEDLINE, EMBASE, and EMBASE CLASSIC) over the last 60 y. The indications for intervention, the technique, and clinical outcomes were reviewed. RESULTS: There were a wide range of indications for TDI. These included reducing rejection after transplantation, treating inflammatory diseases, and reducing chronic failure of the liver, kidney, and heart. The techniques included TD cannulation and lymphovenuous fistula. The outcomes were variable and often equivocal, and this appears to reflect poor design quality. There is clinical equipoise regarding a therapeutic role of (TD lymph drainage in acute pancreatitis, and probably other acute diseases. CONCLUSIONS: Until well-designed clinical trials are undertaken, the clinical benefits of TDIs will remain promising, but uncertain.

Increased ratio of electron transport to net assimilation rate supports elevated isoprenoid emission rate in eucalypts under drought.

Plants undergoing heat and low-CO2 stresses emit large amounts of volatile isoprenoids compared with those in stress-free conditions. One hypothesis posits that the balance between reducing power availability and its use in carbon assimilation determines constitutive isoprenoid emission rates in plants and potentially even their maximum emission capacity under brief periods of stress. To test this, we used abiotic stresses to manipulate the availability of reducing power. Specifically, we examined the effects of mild to severe drought on photosynthetic electron transport rate (ETR) and net carbon assimilation rate (NAR) and the relationship between estimated energy pools and constitutive volatile isoprenoid emission rates in two species of eucalypts: Eucalyptus occidentalis (drought tolerant) and Eucalyptus camaldulensis (drought sensitive). Isoprenoid emission rates were insensitive to mild drought, and the rates increased when the decline in NAR reached a certain species-specific threshold. ETR was sustained under drought and the ETR-NAR ratio increased, driving constitutive isoprenoid emission until severe drought caused carbon limitation of the methylerythritol phosphate pathway. The estimated residual reducing power unused for carbon assimilation, based on the energetic status model, significantly correlated with constitutive isoprenoid emission rates across gradients of drought (r(2) > 0.8) and photorespiratory stress (r(2) > 0.9). Carbon availability could critically limit emission rates under severe drought and photorespiratory stresses. Under most instances of moderate abiotic stress levels, increased isoprenoid emission rates compete with photorespiration for the residual reducing power not invested in carbon assimilation. A similar mechanism also explains the individual positive effects of low-CO2, heat, and drought stresses on isoprenoid emission.

Safety of varenicline tartrate and counseling versus counseling alone for smoking cessation: a randomized controlled trial for inpatients (STOP study).

INTRODUCTION: Inpatient medical settings offer an opportunistic environment for initiating smoking cessation interventions to patients reflecting on their health. Current evidence has shown the superior efficacy of varenicline tartrate (VT) for smoking cessation compared with other tobacco cessation therapies; however, recent evidence also has highlighted concerns about the safety and tolerability of VT. Given these apprehensions, we aimed to evaluate the safety and effectiveness of VT plus quitline-counseling compared to quitline-counseling alone in the inpatient medical setting. METHODS: Adult patients (n = 392, 20-75 years) admitted with a smoking-related illnesses to 3 hospitals were randomized to receive either 12 weeks of varenicline tartrate (titrated from 0.5mg daily to 1mg twice daily) plus quitline-counseling (VT+C), (n = 196) or quitline-counseling alone (n = 196). RESULTS: VT was well tolerated in the inpatient setting among subjects admitted with acute smoking-related illnesses (mean age 52.8±2.89 and 53.7±2.77 years in the VT+C and counseling alone groups, respectively). The most common self-reported adverse event during the 12-week treatment phase was nausea (16.3% in the VT+C group compared with 1.5% in the counseling alone group). Thirteen deaths occurred during the study period (n = 6 were in the VT+C arm compared with n = 7 in the counseling alone arm). All of these subjects had known comorbidities or developed underlying comorbidities. CONCLUSIONS: VT appears to be a safe and well-tolerated opportunistic treatment for inpatient smokers who have related chronic disease. Based on the proven efficacy of varenicline from outpatient studies and our recent inpatient evidence, we suggest it be considered as part of standard care in the hospital setting.

MRI for clinically suspected pediatric appendicitis: case interpretation.

As utilization of MRI for clinically suspected pediatric appendicitis becomes more common, there will be increased focus on case interpretation. The purpose of this pictorial essay is to share our institution's case interpretation experience. MRI findings of appendicitis include appendicoliths, tip appendicitis, intraluminal fluid-debris level, pitfalls of size measurements, and complications including abscesses. The normal appendix and inguinal appendix are also discussed.

Advancements in physiologically based pharmacokinetic modeling for fedratinib: updating dose guidance in the presence of a dual inhibitor of CYP3A4 and CYP2C19.

PURPOSE: A physiologically based pharmacokinetic (PBPK) model for fedratinib was updated and revalidated to bridge a gap between the observed drug-drug interaction (DDI) of a single sub-efficacious dose in healthy participants and the potential DDI in patients with cancer at steady state. The study aimed to establish an appropriate dose for fedratinib in patients coadministered with dual CYP3A4 and CYP2C19 inhibitors, providing quantitative evidence to inform dosing guidance. METHODS: The original minimal PBPK model was developed using Simcyp® Simulator v17. The model was updated by substituting a single distribution rate (Qsac) with 2 separate rates (CLin/CLout) and transitioning to v20. Model parameter updates were further informed with 3 clinical studies, and 3 more studies served as independent validation data. The validated model was applied to simulate potential DDIs between fedratinib and a known dual inhibitor of CYP3A4 and CYP2C19 (fluconazole). RESULTS: Coadministration of fedratinib with fluconazole in patients was predicted to increase fedratinib exposure by < 2-fold in all simulated scenarios. For patients with cancer receiving the approved dose of fedratinib 400 mg once daily along with fluconazole 200 mg daily, the model predicted an approximate 50% increase in fedratinib exposure at steady state. CONCLUSIONS: The updated PBPK model improved description of the observed pharmacokinetics and predicted a low risk of clinically significant DDIs between fedratinib and fluconazole. The quantitative evidence serves as a primary foundation for providing dose guidance in clinical practice for the coadministration of fedratinib with dual CYP3A4 and CYP2C19 inhibitors.