Host kinase regulation of Plasmodium vivax dormant and replicating liver stages.

Upon transmission to the liver, Plasmodium vivax parasites form replicating schizonts, which continue to initiate blood-stage infection, or dormant hypnozoites that reactivate weeks to months after initial infection. P. vivax phenotypes in the field vary significantly, including the ratio of schizonts to hypnozoites formed and the frequency and timing of relapse. Evidence suggests that both parasite genetics and environmental factors underly this heterogeneity. We previously demonstrated that data on the effect of a panel of kinase inhibitors with overlapping targets on Plasmodium liver stage infection, in combination with a computational approach called kinase regression (KiR), can be used to uncover novel host regulators of infection. Here, we applied KiR to evaluate the extent to which P. vivax liver-stage parasites are susceptible to changes in host kinase activity. We identified a role for a subset of host kinases in regulating schizont and hypnozoite infection and schizont size and characterized overlap as well as variability in host phosphosignaling dependencies between parasite forms and across multiple patient isolates. Striking, our data point to variability in host dependencies across P. vivax isolates, suggesting one possible origin of the heterogeneity observed across P. vivax in the field.

Surgical, Radiation, and Systemic Treatments of Patients With Thymic Epithelial Tumors: A Systematic Review.

INTRODUCTION: Thymic epithelial tumors are rare and are classified as thymoma, thymic carcinoma, and thymic neuroendocrine tumors. The objective of this systematic review was to evaluate the treatment options for patients with thymic epithelial tumors. METHODS: This systematic review was developed by Ontario Health (Cancer Care Ontario)'s Program in Evidence-Based Care and by the Lung Cancer Disease Site Group. MEDLINE, EMBASE, and the Cochrane Library were searched for studies comparing surgical, radiotherapy, or systemic treatments against any combination of these treatments in patients with thymic epithelial tumors. Meta-analyses were conducted with clinically homogenous studies. RESULTS: A total of 106 studies were included, mainly from observational studies. There was an overall survival benefit with postoperative radiotherapy for patients with thymic carcinoma (hazard ratio = 0.65, 95% confidence interval: 0.47-0.89) and for patients with thymoma (hazard ratio = 0.70, 95% confidence interval: 0.59-0.82), especially for those with a high risk for mortality. Patients with thymic carcinoma or thymoma had a response to chemotherapy. Selection bias affected the results for studies that evaluated neoadjuvant chemotherapy or minimally invasive surgical techniques. Furthermore, the overall survival benefit found for adjuvant chemotherapy may have been confounded by the administration of postoperative radiotherapy. CONCLUSIONS: For patients with thymoma or thymic carcinoma, the literature is of low quality and subject to bias. There were overall survival benefits with postoperative radiotherapy. The results of this systematic review were used to inform treatment recommendations in a clinical practice guideline. Future large-scale prospective studies that control for confounders are needed.

Surgical, Radiation, and Systemic Treatments of Patients With Thymic Epithelial Tumors: A Clinical Practice Guideline.

INTRODUCTION: The aim of this guideline was to provide recommendations for the most effective therapy for patients with thymic epithelial tumors, including thymoma, thymic carcinoma, and thymic neuroendocrine tumors (NETs). This guideline is intended to be used by all health care professionals managing patients with thymic epithelial tumors. METHODS: The guideline was developed by Ontario Health (Cancer Care Ontario)'s Program in Evidence-Based Care and by the Lung Cancer Disease Site Group through a systematic review of the evidence, expert consensus, and formal internal and external reviews. RESULTS: Evidence-based recommendations were developed to improve the management of patients with thymic epithelial tumors. The guideline includes recommendations for surgical, radiation, and systemic treatments for patients with thymoma, thymic carcinoma, and thymic NETs separated by stage of disease using the TNM staging system. Recommendations for patients with thymic NETs were endorsed from the 2021 National Comprehensive Cancer Network Neuroendocrine and Adrenal Tumors Guideline. CONCLUSIONS: This guideline reflects the new staging system for patients with thymoma and thymic carcinoma and includes supporting evidence from the best available studies.

Prevalence and Workplace Drivers of Burnout in Cancer Care Physicians in Ontario, Canada.

PURPOSE: Provider well-being has become the fourth pillar of the quadruple aim for providing quality care. Exacerbated by the global COVID-19 pandemic, provider well-being has become a critical issue for health care systems worldwide. We describe the prevalence and key system-level drivers of burnout in oncologists in Ontario, Canada. METHODS: This is a cross-sectional survey study conducted in November-December 2019 of practicing cancer care physicians (surgical, medical, radiation, gynecologic oncology, and hematology) in Ontario, Canada. Ontario is Canada's largest province (with a population of 14.5 million), and has a single-payer publicly funded cancer system. The primary outcome was burnout experience assessed through the Maslach Burnout Inventory. RESULTS: A total of 418 physicians completed the questionnaire (response rate was 44% among confirmed oncologists). Seventy-three percent (n = 264 of 362) of oncologists had symptoms of burnout (high emotional exhaustion and/or depersonalization scores). Significant drivers of burnout identified in multivariable regression modeling included working in a hectic or chaotic atmosphere (odds ratio [OR] = 15.5; 95% CI, 3.4 to 71.5; P < .001), feeling unappreciated on the job (OR = 7.9; 95% CI, 2.9 to 21.3; P < .001), reporting poor or marginal control over workload (OR = 7.9; 95% CI, 2.9 to 21.3; P < .001), and not being comfortable talking to peers about workplace stress (OR = 3.0; 95% CI, 1.1 to 7.9; P < .001). Older age (≥ 56 years) was associated with lower odds of burnout (OR = 0.16; 95% CI, 0.1 to 0.4; P < .001). CONCLUSION: Nearly three quarters of participants met predefined standardized criteria for burnout. This number is striking, given the known impact of burnout on provider mental health, patient safety, and quality of care, and suggests Oncologists in Ontario may be a vulnerable group that warrants attention. Health care changes being driven by the COVID-19 pandemic provide an opportunity to rebuild new systems that address drivers of burnout. Creating richer peer-to-peer and leadership engagement opportunities among early- to mid-career individuals may be a worthwhile organizational strategy.

Pure quartic modulational instability in weakly nonlocal birefringent fibers.

The modulational instability (MI) phenomenon is theoretically investigated in birefringent optical media with pure quartic dispersion and weak Kerr nonlocal nonlinearity. We find from the MI gain that instability regions are more expanded due to nonlocality, which is confirmed via direct numerical simulations showing the emergence of Akhmediev breathers (ABs) in the total energy context. In addition, the balanced competition between nonlocality and other nonlinear and dispersive effects exclusively gives the possibility of generating long-lived structures which deepens our understanding of soliton dynamics in pure-quartic dispersive optical systems and opens new investigation routes in fields related to nonlinear optics and lasers.

Detection of Acetylcholine at Nanoscale NPOE/Water Liquid/Liquid Interface Electrodes.

The interface between two immiscible electrolyte solutions (ITIES) has become a very powerful analytical platform for sensing a diverse range of chemicals (e.g., metal ions and neurotransmitters) with the advantage of being able to detect non-redox electroactive species. The ITIES is formed between organic and aqueous phases. Organic solvent identity is crucial to the detection characteristics of the ITIES [half-wave transfer potential (E1/2), potential window range, limit of detection, transfer coefficient (α), standard heterogeneous ion-transfer rate constant (k0), etc.]. Here, we demonstrated, for the first time at the nanoscale, the detection characteristics of the NPOE/water ITIES. Linear detection of the diffusion-limited current at different concentrations of acetylcholine (ACh) was demonstrated with cyclic voltammetry (CV) and i-t amperometry. The E1/2 of ACh transfer at the NPOE/water nanoITIES was -0.342 ± 0.009 V versus the E1/2 of tetrabutylammonium (TBA+). The limit of detection of ACh at the NPOE/water nanoITIES was 37.1 ± 1.5 µM for an electrode with a radius of ∼127 nm. We also determined the ion-transfer kinetics parameters, α and k0, of TBA+ at the NPOE/water nanoITIES by fitting theoretical cyclic voltammograms to experimental voltammograms. This work lays the basis for future cellular studies using ACh detection at the nanoscale and for studies to detect other analytes. The NPOE/water ITIES offers a potential window distinct from that of the 1,2-dichloroethane (DCE)/water ITIES. This unique potential window would offer the ability to detect analytes that are not easily detected at the DCE/water ITIES.

Higher-order dispersion and nonlinear effects of optical fibers under septic self-steepening and self-frequency shift.

We investigate the modulational instability (MI) of a continuous wave (cw) under the combined effects of higher-order dispersions, self steepening and self-frequency shift, cubic, quintic, and septic nonlinearities. Using Maxwell's theory, an extended nonlinear Schrödinger equation is derived. The linear stability analysis of the cw solution is employed to extract an expression for the MI gain, and we point out its sensitivity to both higher-order dispersions and nonlinear terms. In particular, we insist on the balance between the sixth-order dispersion and nonlinearity, septic self-steepening, and the septic self-frequency shift terms. Additionally, the linear stability analysis of cw is confronted with the stability conditions for solitons. Different combinations of the dispersion parameters are proposed that support the stability of solitons and the occurrence of MI. This is confronted with full numerical simulations where the input cw gives rise to a broad range of behaviors, mainly related to nonlinear patterns formation. Interestingly, under the activation of MI, a suitable balance between the sixth-order dispersion and the septic self-frequency shift term is found to highly influence the propagation direction of the optical wave patterns.

Evolution in the Practice of Pediatric Endoscopy and Sedation.

The fields of pediatric gastrointestinal endoscopy and sedation are critically important to the diagnosis and treatment of gastrointestinal (GI) disease in children. Since its inception in the 1970s, pediatric endoscopy has benefitted from tremendous technological innovation related to the design of the endoscope and its associated equipment. Not only that, but expertise among pediatric gastroenterologists has moved the field forward to include a full complement of diagnostic and therapeutic endoscopic procedures in children. In this review, we discuss the remarkable history of pediatric endoscopy and highlight current limitations and future advances in the practice and technology of pediatric endoscopy and sedation.

In Vivo Magnetic Resonance Spectroscopy of Hyperpolarized [1-13 C]Pyruvate and Proton Density Fat Fraction in a Guinea Pig Model of Non-Alcoholic Fatty Liver Disease Development After Life-Long Western Diet Consumption.

BACKGROUND: Alterations in glycolysis are central to the increasing incidence of non-alcoholic fatty liver disease (NAFLD), highlighting a need for in vivo, non-invasive technologies to understand the development of hepatic metabolic aberrations. PURPOSE: To use hyperpolarized magnetic resonance spectroscopy (MRS) and proton density fat fraction (PDFF) magnetic resonance imaging (MRI) techniques to investigate the effects of a chronic, life-long exposure to the Western diet (WD) in an animal model resulting in NAFLD; to investigate the hypothesis that exposure to the WD will result in NAFLD in association with altered pyruvate metabolism. STUDY TYPE: Prospective. ANIMAL MODEL: Twenty-eight male guinea pigs weaned onto a control diet (N = 14) or WD (N = 14). FIELD STRENGTH/SEQUENCE: 3 T; T1-weighted gradient echo, T2-weighted spin-echo, three-dimensional gradient multi-echo fat-water separation (IDEAL-IQ), and broadband point-resolved spectroscopy (PRESS) chemical-shift sequences. ASSESSMENT: Median PDFF was calculated in the liver and hind limbs. [1-13 C]pyruvate dynamic MRS in the liver was quantified by the time-to-peak (TTP) for each metabolite. Animals were euthanized and tissue was analyzed for lipid and cholesterol concentration and enzyme level and activity. STATISTICAL TESTS: Unpaired Student's t-tests were used to determine differences in measurements between the two diet groups. The Pearson correlation coefficient was calculated to determine correlations between measurements. RESULTS: Life-long WD consumption resulted in significantly higher liver PDFF and elevated triglyceride content in the liver. The WD group exhibited a decreased TTP for lactate production, and ex vivo analysis highlighted increased liver lactate dehydrogenase (LDH) activity. DATA CONCLUSION: PDFF MRI results suggest differential fat deposition patterns occurring in animals fed a life-long WD characteristic of lean, or lacking excessive subcutaneous fat, NAFLD. The decreased liver lactate TTP and increased ex vivo LDH activity suggest lipid accumulation occurs in association with a shift from oxidative metabolism to anaerobic glycolytic metabolism in WD-exposed livers. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1.

Postoperative Outcomes Following Total Hip and Knee Arthroplasty in Patients with Pain Catastrophizing, Anxiety, or Depression.

BACKGROUND: The relationship among pain catastrophizing, emotional disorders, and total joint arthroplasty (TJA) outcomes is an emerging area of study. The purpose of this study is to examine the association of these factors with 1-year postoperative pain and functional outcomes. METHODS: A prospective cohort study of preoperative TJA patients using the Pain Catastrophizing Scale and Hospital Anxiety and Depression Scale (HADS-A/HADS-D) was conducted. Postoperative outcomes included Visual Analog Scale (VAS) pain, Oxford, Harris Hip (HHS) and Knee Society (KSS) scores. Median regression was used to assess the pattern of relationship among preoperative clinically relevant catastrophizing (CRC) pain, abnormal HADS, and 1-year postoperative outcomes. RESULTS: We recruited 463 TJA patients, all of which completed 1-year follow-up. At 1 year, CRC-rumination (adjusted median difference 1; 95% confidence interval [CI] 0.31-1.69, P = .005) and abnormal HADS-A (adjusted median difference 1; 95% CI 0.36-1.64, P = .002) were predictors of VAS pain, CRC magnification a predictor of HHS/KSS (adjusted median difference 1.3; 95% CI 5.23-0.11, P = .041), and abnormal HADS-A a predictor of Oxford (adjusted median difference 3.68; 95% CI 1.38-5.99, P = .002). CRC patients demonstrated inferior VAS pain (P = .001), Oxford (P < .0001), and HHS/KSS (P = .025). Abnormal HADS patients demonstrated inferior postoperative VAS (HADS-A, P = .025; HADS-D, P = .030) and Oxford (HADS-A, P = .001; HADS-D, P = .030). However, patients with CRC experienced significant improvement in VAS, Oxford, and HHS/KSS (P < .05) from preoperative to 1 year. Similarly, patients with abnormal HADS showed significant improvement in VAS pain and HHS/KSS (P < .05). CONCLUSION: TJA patients who are anxious, depressed, or pain catastrophizing have inferior preoperative and postoperative pain and function. However, as compared to their preoperative status, clinically significant improvement can be expected following hip/knee arthroplasty.

Pediatric Metastatic Crohn's Disease of the Liver.

Metastatic Crohn's disease (MCD) is the manifestation of Crohn's disease outside of the gastrointestinal tract and most frequently involves mucocutaneous and pulmonary tissues. This is an uncommon phenomenon but is well characterized in the pediatric literature. In contrast, MCD affecting the liver has not previously been described in pediatrics. The pediatric gastroenterologist must be aware of the myriad of Crohn's disease-associated hepatopathies. We herein present the first reported case of pediatric MCD involving the liver and describe our targeted diagnostic evaluation and the patient's response to infliximab-dyyb.

Discrete-trial training performance of behavior interventionists with autism spectrum disorder: A systematic replication and extension.

Further research is needed on strategies to improve employment outcomes for individuals with autism spectrum disorder (ASD). We replicated and extended prior research by examining the acquisition, maintenance, and generalization of discrete-trial training (DTT) performance of adults with ASD who were interested in careers as behavior technicians. Three participants received training on how to implement DTT with children and we assessed the maintenance and generalization of DTT performance in the absence of feedback. Results indicated that procedural integrity generalized across children and targets and maintained for 6 to 17 session days without feedback. Results have implications for the successful employment of individuals with ASD as behavior technicians and for future research on strategies to enhance their performance on the job.

Rare case of remission of a patient with small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) stage IV: Case report.

INTRODUCTION: Small cell carcinoma of the ovary (SCC) is a very rare (less than 1 % of ovarien neoplasia), highly undifferentiated, aggressive malignancy affecting young women and linked to a poor prognosis. Overall survive rate is very low (about 16 %). SCCOHT has recently been shown to be associated with SMARCA4 gene mutations and shows some genetic similarities to malignant rhabdoid tumors (MRT). PRESENTATION OF CASE: After a reminder of the clinical, histological description of the SCCOHT and concensus about the medical management, we describe the rare case of a 22 years old patient with complete remission after diagnosis of un undifferentiated SCCOHT stage IV treated by conservative surgery and high-doses chemotherapy, 30 months after diagnosis. DISCUSSION: Thus far, no standard therapy exists for SCCOHT. Treatment modalities are surgery, chemotherapy, radiotherapy and autologous stem cell transplant after high-dose chemotherapy. Research for new treatments includes target therapy. CONCLUSION: Autologous stem cell transplant after high-dose adjuvant chemotherapy seems to lead to the best survival rates. Invasiveness of the treatment depends on the stage of the disease, age of the patient and her fertility-sparing desire. An international collaboration will be needed to standardise practices due of the small number of patients.

Case presentations and recommendations from the 2018 ITMIG Annual Meeting.

The 9th International Thymic Malignancy Interest Group's (ITMIG) Annual Meeting was held in Seoul, South Korea in October 2018, and in this article, we discuss three of the cases presented and review the radiology imaging and pathology slides. The first two cases involve thymic carcinoma: the first reviews systemic therapy recommendations for non-resectable recurrence and the second case the optimal treatment recommendations after incomplete resection. The third case discusses treatment recommendations for recurrent thymoma after complete resection.

Distribution of Mediastinal Lesions Across Multi-Institutional, International, Radiology Databases.

INTRODUCTION: Mediastinal lesions are uncommon; studies on their distribution are, in general, small and from a single institution. Furthermore, these studies are usually based on pathology or surgical databases and, therefore, miss many lesions that did not undergo biopsy or resection. Our aim was to identify the distribution of lesions in the mediastinum in a large international, multi-institutional cohort. METHODS: At each participating institution, a standardized retrospective radiology database search was performed for interpretations of computed tomography, positron emission tomography-computed tomography, and magnetic resonance imaging scans including any of the following terms: "mediastinal nodule," "mediastinal lesion," "mediastinal mass," or "mediastinal abnormality" (2011-2014). Standardized data were collected. Statistical analysis was performed. RESULTS: Among 3308 cases, thymomas (27.8%), benign mediastinal cysts (20.0%), and lymphomas (16.1%) were most common. The distribution of lesions varied among mediastinal compartments; thymomas (38.3%), benign cysts (16.8%), and neurogenic tumors (53.9%) were the most common lesions in the prevascular, visceral, and paravertebral mediastinum, respectively (p < 0.001). Mediastinal compartment was associated with age; patients with paravertebral lesions were the youngest (p < 0.0001). Mediastinal lesions differed by continent or country, with benign cysts being the most common mediastinal lesions in the People's Republic of China, thymomas in Europe, and lymphomas in North America and Israel (p < 0.001). Benign cysts, thymic carcinomas, and metastases were more often seen in larger hospitals, whereas lymphomas and thymic hyperplasia occurred more often in smaller hospitals (p < 0.01). CONCLUSIONS: Our study confirmed that the spectrum and frequency of mediastinal lesions depend on mediastinal compartment and age. This information provides helpful demographic data and is important when considering the differential diagnosis of a mediastinal lesion.

Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association.

Hypertriglyceridemia (triglycerides 200-499 mg/dL) is relatively common in the United States, whereas more severe triglyceride elevations (very high triglycerides, ≥500 mg/dL) are far less frequently observed. Both are becoming increasingly prevalent in the United States and elsewhere, likely driven in large part by growing rates of obesity and diabetes mellitus. In a 2002 American Heart Association scientific statement, the omega-3 fatty acids (n-3 FAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were recommended (at a dose of 2-4 g/d) for reducing triglycerides in patients with elevated triglycerides. Since 2002, prescription agents containing EPA+DHA or EPA alone have been approved by the US Food and Drug Administration for treating very high triglycerides; these agents are also widely used for hypertriglyceridemia. The purpose of this advisory is to summarize the lipid and lipoprotein effects resulting from pharmacological doses of n-3 FAs (>3 g/d total EPA+DHA) on the basis of new scientific data and availability of n-3 FA agents. In treatment of very high triglycerides with 4 g/d, EPA+DHA agents reduce triglycerides by ≥30% with concurrent increases in low-density lipoprotein cholesterol, whereas EPA-only did not raise low-density lipoprotein cholesterol in very high triglycerides. When used to treat hypertriglyceridemia, n-3 FAs with EPA+DHA or with EPA-only appear roughly comparable for triglyceride lowering and do not increase low-density lipoprotein cholesterol when used as monotherapy or in combination with a statin. In the largest trials of 4 g/d prescription n-3 FA, non-high-density lipoprotein cholesterol and apolipoprotein B were modestly decreased, indicating reductions in total atherogenic lipoproteins. The use of n-3 FA (4 g/d) for improving atherosclerotic cardiovascular disease risk in patients with hypertriglyceridemia is supported by a 25% reduction in major adverse cardiovascular events in REDUCE-IT (Reduction of Cardiovascular Events With EPA Intervention Trial), a randomized placebo-controlled trial of EPA-only in high-risk patients treated with a statin. The results of a trial of 4 g/d prescription EPA+DHA in hypertriglyceridemia are anticipated in 2020. We conclude that prescription n-3 FAs (EPA+DHA or EPA-only) at a dose of 4 g/d (>3 g/d total EPA+DHA) are an effective and safe option for reducing triglycerides as monotherapy or as an adjunct to other lipid-lowering agents.

Improving Timeliness of Oncology Assessment and Cancer Treatment Through Implementation of a Multidisciplinary Lung Cancer Clinic.

PURPOSE: Timely lung cancer care has been associated with improved clinical outcomes and patient satisfaction. We identified improvement opportunities in lung cancer management pathways at Kingston Health Sciences Centre. Quality improvement strategies led to the implementation of a multidisciplinary lung cancer clinic (MDC). METHODS: We set an outcome measure of decreasing the time from diagnosis to first cancer treatment by 10 days within 6 months of clinic implementation. We implemented a weekly MDC that involved respirologists, medical oncologists, and radiation oncologists at which patients with new lung cancer diagnoses were offered concurrent oncology consultation. We used Plan-Do-Study-Act cycles to guide our improvement initiatives. A total of five Plan-Do-Study-Act cycles spanned 14 months and consisted of an MDC pilot clinic, large-scale MDC launching, debriefing meetings, and clinic expansion. Pre-MDC data were analyzed retrospectively to establish baseline and prospectively for improvement. Statistical Process Control XmR(i) charts were used to report data. RESULTS: Since MDC initiation, 128 patients have been seen in 34 MDC clinics (3.8 patients per clinic). Mean days from diagnosis to first oncology assessment decreased from 12.4 days to 3.9 days, and mean days from diagnosis to first cancer treatment decreased from 39.5 to 15.0 days, both of which demonstrated special cause variation. Time to assessment and treatment improved for patients with every stage of lung cancer and for both small-cell and non-small-cell subtypes. CONCLUSION: MDC shortens the time from lung cancer diagnosis to oncology assessment and treatment. Time to treatment improved more than time to oncology assessment, which suggests the improvement is related to benefits beyond faster oncology assessment.