Publications by authors named "Eugene Kim"

362 Publications

The development and stem cells of the esophagus.

Development 2021 Mar 29;148(6). Epub 2021 Mar 29.

Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA

The esophagus is derived from the anterior portion of the foregut endoderm, which also gives rise to the respiratory system. As it develops, the esophageal lining is transformed from a simple columnar epithelium into a stratified squamous cell layer, accompanied by the replacement of unspecified mesenchyme with layers of muscle cells. Studies in animal models have provided significant insights into the roles of various signaling pathways in esophageal development. More recent studies using human pluripotent stem cells (hPSCs) further demonstrate that some of these signaling pathways are conserved in human esophageal development. In addition, a combination of mouse genetics and hPSC differentiation approaches have uncovered new players that control esophageal morphogenesis. In this Review, we summarize these new findings and discuss how the esophagus is established and matures throughout different stages, including its initial specification, respiratory-esophageal separation, epithelial morphogenesis and maintenance. We also discuss esophageal muscular development and enteric nervous system innervation, which are essential for esophageal structure and function.
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http://dx.doi.org/10.1242/dev.193839DOI Listing
March 2021

Regulation and metabolic functions of mTORC1 and mTORC2.

Physiol Rev 2021 Feb 18. Epub 2021 Feb 18.

Biochemistry and Molecular Biology, Rutgers, The State University of New Jersey, United States.

Cells metabolize nutrients for biosynthetic and bioenergetic needs to fuel growth and proliferation. The uptake of nutrients from the environment and their intracellular metabolism is a highly controlled process that involves crosstalk between growth signaling and metabolic pathways. Despite constant fluctuations in nutrient availability and environmental signals, normal cells restore metabolic homeostasis to maintain cellular functions and prevent disease. A central signaling molecule that integrates growth with metabolism is the mechanistic target of rapamycin (mTOR). mTOR is a protein kinase that responds to levels of nutrients and growth signals. mTOR forms two protein complexes, mTORC1, which is sensitive to rapamycin and mTORC2, which is not directly inhibited by this drug. Rapamycin has facilitated the discovery of the various functions of mTORC1 in metabolism. Genetic models that disrupt either mTORC1 or mTORC2 have expanded our knowledge on their cellular, tissue as well as systemic functions in metabolism. Nevertheless, our knowledge on the regulation and functions of mTORC2, particularly in metabolism, has lagged behind. Since mTOR is an important target for cancer, aging and other metabolism-related pathologies, understanding the distinct and overlapping regulation and functions of the two mTOR complexes is vital for the development of more effective therapeutic strategies. This review will discuss the key discoveries and recent findings on the regulation and metabolic functions of the mTOR complexes. We highlight findings from cancer models, but also discuss other examples of the mTOR-mediated metabolic reprogramming occurring in stem and immune cells, type 2 diabetes/obesity, neurodegenerative disorders and aging.
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http://dx.doi.org/10.1152/physrev.00026.2020DOI Listing
February 2021

Bridging-induced phase separation induced by cohesin SMC protein complexes.

Sci Adv 2021 Feb 10;7(7). Epub 2021 Feb 10.

Department of Bionanoscience, Kavli Institute of Nanoscience Delft, Delft University of Technology, Delft, Netherlands.

Structural maintenance of chromosome (SMC) protein complexes are able to extrude DNA loops. While loop extrusion constitutes a fundamental building block of chromosomes, other factors may be equally important. Here, we show that yeast cohesin exhibits pronounced clustering on DNA, with all the hallmarks of biomolecular condensation. DNA-cohesin clusters exhibit liquid-like behavior, showing fusion of clusters, rapid fluorescence recovery after photobleaching and exchange of cohesin with the environment. Strikingly, the in vitro clustering is DNA length dependent, as cohesin forms clusters only on DNA exceeding 3 kilo-base pairs. We discuss how bridging-induced phase separation, a previously unobserved type of biological condensation, can explain the DNA-cohesin clustering through DNA-cohesin-DNA bridges. We confirm that, in yeast cells in vivo, a fraction of cohesin associates with chromatin in a manner consistent with bridging-induced phase separation. Biomolecular condensation by SMC proteins constitutes a new basic principle by which SMC complexes direct genome organization.
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http://dx.doi.org/10.1126/sciadv.abe5905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875533PMC
February 2021

Ilioinguinal/Iliohypogastric Pulsed Radiofrequency for the Treatment of Pediatric Chronic Abdominal Pain: A Case Report.

A A Pract 2021 Feb 5;15(2):e01393. Epub 2021 Feb 5.

From the Division of Pain Medicine, Children's Hospital Los Angeles, Los Angeles, California.

Chronic abdominal pain in the pediatric population has the potential to interfere with all aspects of life and daily functioning. Pain may originate from various sites including the viscera, fascial layers, muscles, or peripheral nerves. The incidence of somatic neuritis, more specifically ilioinguinal and iliohypogastric neuralgia, remains unknown. We report a case highlighting the use of pulsed radiofrequency in the treatment of lower abdominal pain secondary to ilioinguinal and iliohypogastric neuralgia. In carefully selected patients, as part of a multimodal regimen, pulsed radiofrequency can aid recovery by providing effective and long-lasting pain relief, thus allowing time for effective rehabilitation.
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http://dx.doi.org/10.1213/XAA.0000000000001393DOI Listing
February 2021

An Innovative Method of Delivering Nebulized Medications for Perioperative Bronchospasm.

A A Pract 2021 Jan 14;15(1):e01370. Epub 2021 Jan 14.

From the Department of Anesthesiology, Boston Medical Center, Boston, Massachusetts.

Perioperative bronchospasm is a common challenge to anesthetic care. The timely delivery of inhaled medications can be challenging, particularly in pediatric patients and in locations where dedicated resources and respiratory support teams are limited. The delivery of nebulized medication to an intubated patient in the operating room can be difficult. We present an innovative method for delivery of nebulized solutions, in which a jet nebulizer is paired with a Mapleson hyperinflation system.
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http://dx.doi.org/10.1213/XAA.0000000000001370DOI Listing
January 2021

Appendectomy Versus Observation for Appendicitis in Neutropenic Children With Cancer.

Pediatrics 2021 Feb;147(2)

Division of Pediatric Surgery, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin;

Background: Optimal management of neutropenic appendicitis (NA) in children undergoing cancer therapy remains undefined. Management strategies include upfront appendectomy or initial nonoperative management. We aimed to characterize the effect of management strategy on complications and length of stay (LOS) and describe implications for chemotherapy delay or alteration.

Methods: Sites from the Pediatric Surgery Oncology Research Collaborative performed a retrospective review of children with NA over a 6-year period.

Results: Sixty-six children, with a median age of 11 years (range 1-17), were identified with NA while undergoing cancer treatment. The most common cancer diagnoses were leukemia (62%) and brain tumor (12%). Upfront appendectomy was performed in 41% of patients; the remainder had initial nonoperative management. Rates of abscess or perforation at diagnosis were equivalent in the groups (30% vs 24%; = .23). Of patients who had initial nonoperative management, 46% (17 of 37) underwent delayed appendectomy during the same hospitalization. Delayed appendectomy was due to failure of initial nonoperative management in 65% ( = 11) and count recovery in 35% ( = 6). Cancer therapy was delayed in 35% ( = 23). Initial nonoperative management was associated with a delay in cancer treatment (46% vs. 22%, = .05) and longer LOS (29 vs 12 days; = .01). Patients who had initial nonoperative management and delayed appendectomy had a higher rate of postoperative complications ( < .01).

Conclusions: In pediatric patients with NA from oncologic treatment, upfront appendectomy resulted in lower complication rates, reduced LOS, and fewer alterations in chemotherapy regimens compared to initial nonoperative management.
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http://dx.doi.org/10.1542/peds.2020-027797DOI Listing
February 2021

Radiation dose reduction in extremity multi-detector CT: A comparison of image quality with a standard dose protocol.

Eur J Radiol 2021 Feb 11;135:109405. Epub 2020 Nov 11.

Department of Orthopaedic Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Purpose: To analyze the quantitative and qualitative image quality of computed tomography (CT) of the extremities (shoulder, wrist, pelvis, and ankle joints) with low-dose radiation and standard-dose radiation.

Materials And Methods: In this study, we included 400 individuals who underwent CT of the extremities, comprising 50 cases of each joint (shoulder, wrist, pelvis, and ankle) at low and standard dose regimens. Low-dose CTs were performed using identical voltage and parameters with the exception of decreased (half of standard dose) tube current. Low-dose and standard-dose images were compared in terms of radiation dose, objective image quality according to the standard deviation (SD) of the Hounsfield unit value of the medulla, cortex, muscle, subcutaneous fat, and air, and subjective image quality according to noise, sharpness, diagnostic acceptability, and artifacts.

Results: In the shoulder and pelvis, the mean value of the SD for all tissue on low dose CT images was significantly higher than that of standard dose CT, except for the SD of cortex in the shoulder joint and marrow in the pelvis. In the wrist, the mean value of the SD for all tissue was not significantly different between low dose and standard CT (p > 0.05). In the ankle, the mean value of the SD of the medulla and cortex was not different (p > 0.05), but the remaining measurements were significantly higher in low dose CT. Subjective image quality in the shoulder and pelvis were significantly reduced in low dose CT. In the wrist, all categories of subjective image quality except artifacts were similar. In the ankle, all categories of subjective image quality except for artifacts were degraded in low dose CT.

Conclusions: Objective image noise is more increased in low dose CT images of the shoulder and pelvis. Although diagnostic performance was acceptable, mean subjective image quality also decreased. In the wrist, objective image noise and subjective image quality were not degraded in low dose CT. In the ankle, some measurements of objective and subjective image quality were similar between low dose and standard dose CT.
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http://dx.doi.org/10.1016/j.ejrad.2020.109405DOI Listing
February 2021

Initiation of immunotherapy with activated natural killer cells and anti-GD2 antibody dinutuximab prior to resection of primary neuroblastoma prolongs survival in mice.

J Immunother Cancer 2020 12;8(2)

Division of Pediatric Surgery, Department of Surgery, Children's Hospital Los Angeles, Los Angeles, California, USA

Background: Immunotherapy with anti-disialoganglioside dinutuximab has improved survival for children with high-risk neuroblastoma (NB) when given after induction chemotherapy and surgery. However, disease recurrence and resistance persist. Dinutuximab efficacy has not been evaluated when initiated before primary tumor removal. Using a surgical mouse model of human NB, we examined if initiating dinutuximab plus ex vivo-activated natural killer (aNK) cells before resection of the primary tumor improves survival.

Methods: In vitro, human NB cells (SMS-KCNR-Fluc, CHLA-255-Fluc) were treated with dinutuximab and/or aNK cells and cytotoxicity was measured. In vivo, NB cells (SMS-KCNR-Fluc, CHLA-255-Fluc, or COG-N-415x PDX) were injected into the kidney of NOD-scid gamma mice. Mice received eight intravenous infusions of aNK cells plus dinutuximab beginning either 12 days before or 2 days after resection of primary tumors. Tumors in control mice were treated by resection alone or with immunotherapy alone. Disease was quantified by bioluminescent imaging and survival was monitored. aNK cell infiltration into primary tumors was quantified by flow cytometry and immunohistochemistry at varying timepoints.

Results: In vitro, aNK cells and dinutuximab were more cytotoxic than either treatment alone. In vivo, treatment with aNK cells plus dinutuximab prior to resection of the primary tumor was most effective in limiting metastatic disease and prolonging survival. aNK cell infiltration into xenograft tumors was observed after 1 day and peaked at 5 days following injection.

Conclusion: Dinutuximab plus aNK cell immunotherapy initiated before resection of primary tumors decreases disease burden and prolongs survival in an experimental mouse model of NB. These findings support the clinical investigation of this treatment strategy during induction therapy in patients with high-risk NB.
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http://dx.doi.org/10.1136/jitc-2020-001560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751216PMC
December 2020

BCL2 Expression in First-Line Diffuse Large B-Cell Lymphoma Identifies a Patient Population With Poor Prognosis.

Clin Lymphoma Myeloma Leuk 2021 Apr 10;21(4):267-278.e10. Epub 2020 Nov 10.

Multidisciplinary Oncology Outpatient Clinic, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy.

Introduction: The prognostic value of B-cell lymphoma 2 (BCL2) expression in de novo diffuse large B-cell lymphoma (DLBCL) treated with immunochemotherapy is of interest to define a target patient population for clinical development of BCL2 inhibitors. We aimed to develop a reproducible immunohistochemistry algorithm and assay to determine BCL2 protein expression and assess the prognostic value of BCL2 in newly diagnosed DLBCL cohorts.

Patients And Methods: The prospectively defined algorithm incorporated BCL2 staining intensity and percentage of BCL2-positive cells. Functionally relevant cutoffs were based on the sensitivity of lymphoma cell lines to venetoclax. This assay was highly reproducible across laboratories. The prognostic impact of BCL2 expression was assessed in DLBCL patients from the phase 3 MAIN (n = 230) and GOYA (n = 366) trials, and a population-based registry (n = 310).

Results: Approximately 50% of tumors were BCL2 positive, with a higher frequency in high International Prognostic Index (IPI) and activated B-cell-like DLBCL subgroups. BCL2 expression was associated with poorer progression-free survival in the MAIN study (hazard ratio [HR], 1.66; 95% confidence interval [CI], 0.81-3.40; multivariate Cox regression adjusted for IPI and cell of origin). This trend was confirmed in the GOYA and registry cohorts in adjusted multivariate analyses (GOYA: HR, 1.72; 95% CI, 1.05-2.82; registry: HR, 1.89; 95% CI, 1.29-2.78). Patients with BCL2 immunohistochemistry-positive and IPI-high disease had the poorest prognosis: 3-year progression-free survival rates were 51% (GOYA) and 37% (registry).

Conclusion: Findings support use of our BCL2 immunohistochemistry scoring system and assay to select patients with BCL2-positive tumors for future studies.
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http://dx.doi.org/10.1016/j.clml.2020.11.004DOI Listing
April 2021

Engaging Parents in Analgesia Selection and Racial/Ethnic Differences in Analgesia Given to Pediatric Patients Undergoing Urologic Surgery.

Children (Basel) 2020 Dec 7;7(12). Epub 2020 Dec 7.

Department of Anesthesiology Critical Care Medicine, Division of Pain Medicine, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.

Background: Family-centered care aims to consider family preferences and values in care delivery. Our study examines parent decisions regarding anesthesia type (caudal regional block or local anesthesia) among a diverse sample of children undergoing urologic surgeries. Differences in anesthesia type were examined by known predictors of health disparities, including child race/ethnicity, parental English proficiency, and a proxy for household income.

Methods: A retrospective review of 4739 patients (including 25.4% non-Latino/a White, 8.7% non- Latino/a Asians, 7.3% non-Latino/a Black, 23.1% Latino/a, and 35.4% others) undergoing urologic surgeries from 2016 to 2020 using univariate and logistic regression analyses.

Results: 62.1% of Latino/a parents and 60.8% of non-Latino/a Black parents did not agree to a regional block. 65.1% of Spanish-speaking parents with limited English Proficiency did not agree to a regional block. Of parents from households below poverty lines, 61.7% did not agree to a caudal regional block. In regression analysis, Latino/a and non- Latino/a Black youth were less likely to receive caudal regional block than non- Latino/a White patients.

Conclusions: We found disparities in the use of pediatric pain management techniques. Understanding mechanisms underlying Latino/a and non- Latino/a Black parental preferences may help providers reduce these disparities.
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http://dx.doi.org/10.3390/children7120277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762314PMC
December 2020

Behavioral, neuroanatomical, and molecular correlates of resilience and susceptibility to maternal immune activation.

Mol Psychiatry 2021 02 23;26(2):396-410. Epub 2020 Nov 23.

Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland.

Infectious or noninfectious maternal immune activation (MIA) is an environmental risk factor for psychiatric and neurological disorders with neurodevelopmental etiologies. Whilst there is increasing evidence for significant health consequences, the effects of MIA on the offspring appear to be variable. Here, we aimed to identify and characterize subgroups of isogenic mouse offspring exposed to identical MIA, which was induced in C57BL6/N mice by administration of the viral mimetic, poly(I:C), on gestation day 12. Cluster analysis of behavioral data obtained from a first cohort containing >150 MIA and control offspring revealed that MIA offspring could be stratified into distinct subgroups that were characterized by the presence or absence of multiple behavioral dysfunctions. The two subgroups also differed in terms of their transcriptional profiles in cortical and subcortical brain regions and brain networks of structural covariance, as measured by ex vivo structural magnetic resonance imaging (MRI). In a second, independent cohort containing 50 MIA and control offspring, we identified a subgroup of MIA offspring that displayed elevated peripheral production of innate inflammatory cytokines, including IL-1β, IL-6, and TNF-α, in adulthood. This subgroup also showed significant impairments in social approach behavior and sensorimotor gating, whereas MIA offspring with a low inflammatory cytokine status did not. Taken together, our results highlight the existence of subgroups of MIA-exposed offspring that show dissociable behavioral, transcriptional, brain network, and immunological profiles even under conditions of genetic homogeneity. These data have relevance for advancing our understanding of the variable neurodevelopmental effects induced by MIA and for biomarker-guided approaches in preclinical psychiatric research.
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http://dx.doi.org/10.1038/s41380-020-00952-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850974PMC
February 2021

Guidelines for Opioid Prescribing in Children and Adolescents After Surgery: An Expert Panel Opinion.

JAMA Surg 2021 Jan;156(1):76-90

Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Children's Hospital Los Angeles, Los Angeles, California.

Importance: Opioids are frequently prescribed to children and adolescents after surgery. Prescription opioid misuse is associated with high-risk behavior in youth. Evidence-based guidelines for opioid prescribing practices in children are lacking.

Objective: To assemble a multidisciplinary team of health care experts and leaders in opioid stewardship, review current literature regarding opioid use and risks unique to pediatric populations, and develop a broad framework for evidence-based opioid prescribing guidelines for children who require surgery.

Evidence Review: Reviews of relevant literature were performed including all English-language articles published from January 1, 1988, to February 28, 2019, found via searches of the PubMed (MEDLINE), CINAHL, Embase, and Cochrane databases. Pediatric was defined as children younger than 18 years. Animal and experimental studies, case reports, review articles, and editorials were excluded. Selected articles were graded using tools from the Oxford Centre for Evidence-based Medicine 2011 levels of evidence. The Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument was applied throughout guideline creation. Consensus was determined using a modified Delphi technique.

Findings: Overall, 14 574 articles were screened for inclusion, with 217 unique articles included for qualitative synthesis. Twenty guideline statements were generated from a 2-day in-person meeting and subsequently reviewed, edited, and endorsed externally by pediatric surgical specialists, the American Pediatric Surgery Association Board of Governors, the American Academy of Pediatrics Section on Surgery Executive Committee, and the American College of Surgeons Board of Regents. Review of the literature and guideline statements underscored 3 primary themes: (1) health care professionals caring for children who require surgery must recognize the risks of opioid misuse associated with prescription opioids, (2) nonopioid analgesic use should be optimized in the perioperative period, and (3) patient and family education regarding perioperative pain management and safe opioid use practices must occur both before and after surgery.

Conclusions And Relevance: These are the first opioid-prescribing guidelines to address the unique needs of children who require surgery. Health care professionals caring for children and adolescents in the perioperative period should optimize pain management and minimize risks associated with opioid use by engaging patients and families in opioid stewardship efforts.
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http://dx.doi.org/10.1001/jamasurg.2020.5045DOI Listing
January 2021

Implications of Tumor Characteristics and Treatment Modality on Local Recurrence and Functional Outcomes in Children with Chest Wall Sarcoma: A Pediatric Surgical Oncology Research Collaborative Study.

Ann Surg 2020 Nov 4. Epub 2020 Nov 4.

Division of Pediatric Surgery, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.

Objective: To determine the impact of tumor characteristics and treatment approach on (1) local recurrence, (2) scoliosis development and (3) patient-reported quality of life in children with sarcoma of the chest wall.

Summary Background Data: Children with chest wall sarcoma require multimodal therapy including chemotherapy, surgery and/or radiation. Despite aggressive therapy which places them at risk for functional impairment and scoliosis, these patients are also at significant risk for local recurrence.

Methods: A multi-institutional review of 175 children (median age 13 years) with chest wall sarcoma treated at seventeen Pediatric Surgical Oncology Research Collaborative institutions between 2008-2017 was performed. Patient-reported quality of life was assessed prospectively using PROMIS surveys.

Results: The most common diagnoses were Ewing sarcoma (67%) and osteosarcoma (9%). Surgical resection was performed in 85% and radiation in 55%. A median of 2 ribs were resected (IQR = 1-3), and number of ribs resected did not correlate with margin status (p = 0.36). Local recurrence occurred in 23% and margin status was the only predictive factor (HR 2.24, p = 0.039). With a median follow-up of 5 years, 13% developed scoliosis (median Cobb angle 26) and 5% required corrective spine surgery. Scoliosis was associated with posterior rib resection (HR 8.43; p = 0.003) and increased number of ribs resected (HR 1.78; p = 0.02). Overall, patient-reported quality of life is not impaired following chest wall tumor resection.

Conclusions: Local recurrence occurs in one-quarter of children with chest wall sarcoma and is independent of tumor type. Scoliosis occurs in 13% of patients, but patient-reported quality of life is excellent.
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http://dx.doi.org/10.1097/SLA.0000000000004579DOI Listing
November 2020

Graphene oxide/mussel foot protein composites for high-strength and ultra-tough thin films.

Sci Rep 2020 11 5;10(1):19082. Epub 2020 Nov 5.

Department of Energy, Environmental and Chemical Engineering, Washington University in St. Louis, One Brookings Drive, Saint Louis, MO, 63130, USA.

Graphene oxide (GO)-based composite materials have become widely popular in many applications due to the attractive properties of GO, such as high strength and high electrical conductivity at the nanoscale. Most current GO composites use organic polymer as the matrix material and thus, their synthesis suffers from the use of organic solvents or surfactants, which raise environmental and energy-consumption concerns. Inspired by mussel foot proteins (Mfp) secreted by the saltwater mussel, Mytilus galloprovincialis and by recent advances in microbial protein production, we developed an aqueous-based green synthesis strategy for preparing GO/Mfp film composites. These GO/Mfp films display high tensile strength (134-158 MPa), stretchability (~ 26% elongation), and high toughness (20-24 MJ/m), beyond the capabilities of many existing GO composites. Renewable production of Mfp proteins and the facile fabrication process described provides a new avenue for composite material synthesis, while the unique combination of mechanical properties of GO/Mfp films will be attractive for a range of applications.
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http://dx.doi.org/10.1038/s41598-020-76004-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644685PMC
November 2020

Palmar Rash in a Young Child.

Am Fam Physician 2020 11;102(9):565-566

Fort Belvoir Community Hospital, Fort Belvoir, VA, USA.

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November 2020

Comparison of Pupillometry With Surgical Pleth Index Monitoring on Perioperative Opioid Consumption and Nociception During Propofol-Remifentanil Anesthesia: A Prospective Randomized Controlled Trial.

Anesth Analg 2020 11;131(5):1589-1598

Department of Anesthesiology and Pain Medicine, Hanyang University Medical Center, College of Medicine, Hanyang University, Seoul, Republic of Korea.

Background: Intraoperative monitoring with pupillometry has shown promising results for nociception/antinociception balance monitoring. However, its benefits in clinical practice remain unproven. The aim of this study was to evaluate the efficacy of intraoperative pupillometry monitoring on intraoperative opioid consumption and postoperative pain compared to surgical pleth index (SPI), another widely investigated monitoring.

Methods: American Society of Anesthesiologists (ASA) I-II patients scheduled for elective laparoscopic cholecystectomy were included. This prospective, parallel-arm, single-center study was conducted in 2 steps. First, we evaluated the feasibility of using pupillometry and SPI monitoring compared with conventional hemodynamic monitoring. Next, a parallel-arm, double-blind randomized study compared the peak postoperative pain measured with numerical rating scale (NRS) from 0 (no pain) to 10 (extreme pain) as a primary outcome between pupillometry (pupillometry group, n = 43) and SPI monitoring (SPI group, n = 43) using Mann-Whitney U test. Secondary outcomes included intraoperative remifentanil consumption, postoperative opioid responsiveness (a decrease in NRS by ≥1 after fentanyl administrations), number of analgesic administrations, and opioid-related complications.

Results: In the preliminary study (n = 50), remifentanil consumption was less under pupillometry monitoring compared to SPI monitoring, and peak postoperative pain was lower under pupillometry compared to conventional monitoring. In the main study (n = 86), peak postoperative pain and intraoperative remifentanil consumption were lower in the pupillometry group (median [first to third quartile], 5 [4-6]; mean ± standard deviation [SD], 0.078 ± 0.019 μg·kg·minute) compared to the SPI group (7 [5-8] and 0.0130 ± 0.051 μg·kg·minute; P < .001), with the median difference in peak postoperative pain of -1 and its 95% confidence interval between -2 and -0.5. The pupillometry group had better responsiveness to fentanyl (84.6% vs 61.0%; P = .005) and lower number of analgesic administrations (2 [1-2] vs 2 [1-3]; P = .048) compared to the SPI group.

Conclusions: Intraoperative pupillometry monitoring reduced intraoperative remifentanil consumption and postoperative pain. It may be an alternative option for intraoperative opioid control under general anesthesia in adult patients.
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http://dx.doi.org/10.1213/ANE.0000000000004958DOI Listing
November 2020

Impact of the coronavirus disease 2019 pandemic on surgical research and lessons for the future.

Surgery 2021 02 19;169(2):257-263. Epub 2020 Sep 19.

Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Background: The current coronavirus disease 2019 pandemic has had an unprecedented impact on all physicians and has resulted in dramatic changes to clinical and research operations. No study has yet looked at the impact of coronavirus disease 2019 on the surgical research community. In this study, we sought to understand the impact of the pandemic and its associated restrictions on academic surgeons.

Methods: We surveyed members of the Association for Academic Surgery and the Society of University Surgeons. Survey questions included demographics, current challenges to basic and clinical research activities, attitudes toward remote work and productivity maintenance, and the solutions implemented to maintain productivity.

Results: Of 301 respondents, 70% cited a negative impact on research productivity due to mandatory building shutdowns, minimized personnel as a result of social distancing, and suspensions of animal work and clinical trials, with senior faculty and division chiefs and chairs more likely to report a negative impact (P = .001). Only 11% of respondents are documenting their financial losses, and only 19% indicated they received appropriate guidance regarding why and how to monitor the financial impact of the pandemic. Researchers have attempted to maintain research productivity through a focus on remote work, including manuscript writing, grant writing, and data analysis. Some participants have found silver linings, including more time to dedicate to research and family as a result of fewer clinical duties.

Conclusion: Productivity strategies developed during the pandemic, including writing, remote work and meetings, and structured scheduling, are lessons that will allow the surgical research community to be resilient in the face of future disruptions.
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http://dx.doi.org/10.1016/j.surg.2020.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502013PMC
February 2021

Prognostic impact of somatic mutations in diffuse large B-cell lymphoma and relationship to cell-of-origin: data from the phase III GOYA study.

Haematologica 2020 09 1;105(9):2298-2307. Epub 2020 Sep 1.

Oncology Biomarker Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Diffuse large B-cell lymphoma represents a biologically and clinically heterogeneous diagnostic category with well-defined cell-of-origin subtypes. Using data from the GOYA study (NCT01287741), we characterized the mutational profile of diffuse large B-cell lymphoma and evaluated the prognostic impact of somatic mutations in relation to cell-of-origin. Targeted DNA next-generation sequencing was performed in 499 formalin-fixed paraffin-embedded tissue biopsies from previously untreated patients. Prevalence of genetic alterations/mutations was examined. Multivariate Cox regression was used to evaluate the prognostic effect of individual genomic alterations. Of 465 genes analyzed, 59 were identified with mutations occurring in at least 10 of 499 patients (≥2% prevalence); 334 additional genes had mutations occurring in ≥1 patient. Single nucleotide variants were the most common mutation type. On multivariate analysis, BCL2 alterations were most strongly associated with shorter progression-free survival (multivariate hazard ratio: 2.6; 95% confidence interval: 1.6 to 4.2). BCL2 alterations were detected in 102 of 499 patients; 92 had BCL2 translocations, 90% of whom had germinal center B-cell-like diffuse large B-cell lymphoma. BCL2 alterations were also significantly correlated with BCL2 gene and protein expression levels. Validation of published mutational subsets revealed consistent patterns of co-occurrence, but no consistent prognostic differences between subsets. Our data confirm the molecular heterogeneity of diffuse large B-cell lymphoma, with potential treatment targets occurring in distinct cell-of-origin subtypes. clinicaltrials.gov identifier: NCT01287741.
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http://dx.doi.org/10.3324/haematol.2019.227892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556630PMC
September 2020

Roles of OB-Fold Proteins in Replication Stress.

Front Cell Dev Biol 2020 11;8:574466. Epub 2020 Sep 11.

Department of Cancer Biology, Cardinal Bernardin Cancer Center, Loyola University Chicago Stritch School of Medicine, Maywood, IL, United States.

Accurate DNA replication is essential for maintaining genome stability. However, this stability becomes vulnerable when replication fork progression is stalled or slowed - a condition known as replication stress. Prolonged fork stalling can cause DNA damage, leading to genome instabilities. Thus, cells have developed several pathways and a complex set of proteins to overcome the challenge at stalled replication forks. Oligonucleotide/oligosaccharide binding (OB)-fold containing proteins are a group of proteins that play a crucial role in fork protection and fork restart. These proteins bind to single-stranded DNA with high affinity and prevent premature annealing and unwanted nuclease digestion. Among these OB-fold containing proteins, the best studied in eukaryotic cells are replication protein A (RPA) and breast cancer susceptibility protein 2 (BRCA2). Recently, another RPA-like protein complex CTC1-STN1-TEN1 (CST) complex has been found to counter replication perturbation. In this review, we discuss the latest findings on how these OB-fold containing proteins (RPA, BRCA2, CST) cooperate to safeguard DNA replication and maintain genome stability.
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http://dx.doi.org/10.3389/fcell.2020.574466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517361PMC
September 2020

Neuroprotection by remote ischemic conditioning in the setting of acute ischemic stroke: a preclinical two-centre study.

Sci Rep 2020 10 9;10(1):16874. Epub 2020 Oct 9.

The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK.

Reperfusion is the only existing strategy for patients with acute ischemic stroke, however it causes further brain damage itself. A feasible therapy targeting reperfusion injury is remote ischemic conditioning (RIC). This was a two-centre, randomized, blinded international study, using translational imaging endpoints, aimed to examine the neuroprotective effects of RIC in ischemic stroke model. 80 male rats underwent 90-min middle cerebral artery occlusion. RIC consisted of 4 × 5 min cycles of left hind limb ischemia. The primary endpoint was infarct size measured on T2-weighted MRI at 24 h, expressed as percentage of the area-at-risk. Secondary endpoints were: hemispheric space-modifying edema, infarct growth between per-occlusion and 24 h MRI, neurofunctional outcome measured by neuroscores. 47 rats were included in the analysis after applying pre-defined inclusion criteria. RIC significantly reduced infarct size (median, interquartile range: 19% [8%; 32%] vs control: 40% [17%; 59%], p = 0.028). This effect was still significant after adjustment for apparent diffusion coefficient lesion size in multivariate analysis. RIC also improved neuroscores (6 [3; 8] vs control: 9 [7; 11], p = 0.032). Other secondary endpoints were not statistically different between groups. We conclude that RIC in the setting of acute ischemic stroke in rats is safe, reduces infarct size and improves functional recovery.
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http://dx.doi.org/10.1038/s41598-020-74046-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547701PMC
October 2020

Frontal electroencephalogram activity during emergence from general anaesthesia in children with and without emergence delirium.

Br J Anaesth 2021 Jan 1;126(1):293-303. Epub 2020 Oct 1.

Department of Anaesthesiology and Pain Medicine, Hanyang University Medical Centre, College of Medicine, Hanyang University, Seoul, Republic of Korea. Electronic address:

Background: Emergence delirium (ED) in children after general anaesthesia causes significant distress in patients, their family members, and clinicians; however, electroencephalogram (EEG) markers predicting ED have not been fully investigated.

Methods: This prospective, single-centre observational study enrolled children aged 2-10 yr old under sevoflurane anaesthesia. ED was assessed according to Diagnostic and Statistical Manual of Mental Disorders (DSM) IV or 5 criteria. The relative power of low-frequency (delta and theta) and high-frequency (alpha and beta) EEG waves during the emergence period was compared between the children with and without ED. The linear relationships between the relative power and peak Paediatric Assessment of Emergence Delirium (PAED) score were investigated.

Results: Among the 60 patients, 22 developed ED (ED group), whereas the other 38 did not (non-ED group). The relative power of the delta wave was higher (mean [standard deviation], 0.579 [0.083] vs 0.453 [0.090], respectively, P<0.001) in the ED group, whereas that of the alpha and beta waves was lower in the ED group, than in the non-ED group (0.155 [0.063] vs 0.218 [0.088], P=0.005 and 0.114 [0.069] vs 0.186 [0.070], P<0.001, respectively). The areas under the receiver operating characteristic curves of the relative power of the delta wave, low-to-high frequency power ratio, and delta-to-alpha ratio were 0.837 (95% confidence interval, 0.737-0.938), 0.835 (0.735-0.934), and 0.768 (0.649-0.887), respectively. The relative power of the delta wave and the two ratios had a positive linear relationship with the peak PAED scores.

Conclusions: Paediatric patients developing ED have increased low-frequency (delta) frontal EEG activity with reduced high-frequency (alpha and beta) activity during emergence from general anaesthesia.

Clinical Trial Registration: NCT03797274.
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http://dx.doi.org/10.1016/j.bja.2020.07.060DOI Listing
January 2021

Continuous Intravenous Lidocaine Provides Effective Pain Control in a Palliative Child: A Case Report.

A A Pract 2020 Sep;14(11):e01305

From the Department of Anesthesiology Critical Care Medicine, Children's Hospital Los Angeles, Los Angeles, California.

Lidocaine infusion is often used as part of a perioperative, multimodal pain management plan. We present its use to treat an 8-year-old child with devastating headaches. His symptoms stemmed from an inoperable supratentorial ependymoma that was causing thalamic bleeding and increased intracranial pressure. Many commonly used pain medications are associated with deleterious side effects such as bleeding and excessive sedation. These effects prevent lucidity for interactions, confound neurologic examination. A lidocaine infusion resulted in significant pain relief without these negative side effects. We discuss lidocaine infusion use and considerations for children suffering from intractable headaches.
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http://dx.doi.org/10.1213/XAA.0000000000001305DOI Listing
September 2020

A smartphone-based particle diffusometry platform for sub-attomolar detection of Vibrio cholerae in environmental water.

Biosens Bioelectron 2020 Nov 8;167:112497. Epub 2020 Aug 8.

Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, 47907, USA. Electronic address:

Each year, 3.4 million people die from waterborne diseases worldwide. Development of a rapid and portable platform for detecting and monitoring waterborne pathogens would significantly aid in reducing the incidence and spread of infectious diseases. By combining optical methods and smartphone technology with molecular assays, the sensitivity required to detect exceedingly low concentrations of waterborne pathogens can readily be achieved. Here, we implement smartphone-based particle diffusometry (PD) detection of loop-mediated isothermal amplification (LAMP) targeting the waterborne pathogen Vibrio cholerae (V. cholerae). By measuring the diffusion of 400 nm streptavidin-coated fluorescent nanoparticles imaged at 68X magnification on a smartphone, we can detect as few as 6 V. cholerae cells per reaction (0.66 aM) in just 35 minutes. In a double-blinded study with 132 pond water samples, we establish a 91.8% sensitivity, 95.2% specificity, and 94.3% accuracy of the smartphone-based PD platform for detection of V. cholerae. Together, these results demonstrate the utility of this smartphone-based PD platform for rapid and sensitive detection of V. cholerae at the point of use.
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http://dx.doi.org/10.1016/j.bios.2020.112497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532658PMC
November 2020

Thoracoscopy vs thoracotomy for the management of metastatic osteosarcoma: A Pediatric Surgical Oncology Research Collaborative Study.

Int J Cancer 2021 Mar 31;148(5):1164-1171. Epub 2020 Aug 31.

Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.

Complete surgical resection of pulmonary metastatic disease in patients with osteosarcoma is crucial to long-term survival. Open thoracotomy allows palpation of nodules not identified on imaging but the impact on survival is unknown. The objective of this study was to compare overall survival (OS) and pulmonary disease-free survival (DFS) in children who underwent thoracotomy vs thoracoscopic surgery for pulmonary metastasectomy. A multi-institutional collaborative group retrospectively reviewed 202 pediatric patients with osteosarcoma who underwent pulmonary metastasectomy by thoracotomy (n = 154) or thoracoscopy (n = 48). Results were analyzed by Kaplan-Meier survival estimates and multivariate Cox proportional hazard regression models. With median follow-up of 45 months, 135 (67.5%) patients had a pulmonary relapse and 95 (47%) patients were deceased. Kaplan-Meier analysis showed no significant difference in 5-year pulmonary DFS (25% vs 38%; P = .18) or OS (49% vs 42%, P = .37) between the surgical approaches of thoracotomy and thoracoscopy. In Cox regression analysis controlling for other factors impacting outcome, there was a significantly increased risk of mortality (HR 2.11; P = .027; 95% CI 1.09-4.09) but not pulmonary recurrence (HR 0.96; P = .90; 95% CI 0.52-1.79) with a thoracoscopic approach. However, in the subset analysis limited to patients with oligometastatic disease, thoracoscopy had no increased risk of mortality (HR 1.16; P = .62; 0.64-2.11). In conclusion, patients with metastatic osteosarcoma and limited pulmonary disease burden demonstrate comparable outcomes after thoracotomy and thoracoscopy for metastasectomy. While significant selection bias in these surgical cohorts limits the generalizability of the conclusions, clinical equipoise for a randomized clinical trial in patients with oligometastatic disease is supported.
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http://dx.doi.org/10.1002/ijc.33264DOI Listing
March 2021

Ultrasound evaluation of postsurgical shoulder after rotator cuff repair: comparison of clinical results.

Acta Radiol 2020 Aug 16:284185120948494. Epub 2020 Aug 16.

Department of Orthopaedic Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Background: The relationship between the imaging parameters on postoperative ultrasound (US) other than repaired tendon integrity with clinical outcome such as postoperative residual pain has not been well defined.

Purpose: To investigate whether the repaired tendon thickness and subdeltoid fluid collection after rotator cuff repair are correlated with early postoperative clinical outcome.

Material And Methods: This retrospective study included 54 patients who underwent repair of the arthroscopic rotator cuff either by suture-bridge or single-row technique and postoperative US. We assessed the relationship between the sonographic parameters, including repaired supraspinatus tendon thickness and subdeltoid fluid collection, with the clinical outcome represented by the Korean Shoulder Scoring system (KSS) score using correlation coefficients (R). Also, the subgroup analysis was done to assess the differences by surgical technique and patients' age.

Results: There was a significant inverse relationship between the amount of subdeltoid fluid collection and degree of self-assessed pain improvement of the patients ( < 0.05), although every KSS category showed statistically insignificant tendency of inverse relationship with the fluid thickness. However, there was no statistically significant relationship between the thickness of repaired supraspinatus tendon and KSS scores. In patients aged >60 years, a statistically significant inverse relationship between thickness of subdeltoid fluid collection and difference value of the KSS scores in category of function was observed with both interpreters ( = 0.015 and  = 0.04, respectively).

Conclusion: Subdeltoid fluid collection measured on US after repair of the arthroscopic rotator cuff in the early postoperative period has significant association with the patients' subjective clinical outcome.
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http://dx.doi.org/10.1177/0284185120948494DOI Listing
August 2020

Cooperative carbon capture and steam regeneration with tetraamine-appended metal-organic frameworks.

Science 2020 07;369(6502):392-396

Department of Chemistry, University of California, Berkeley, CA 94720, USA.

Natural gas has become the dominant source of electricity in the United States, and technologies capable of efficiently removing carbon dioxide (CO) from the flue emissions of natural gas-fired power plants could reduce their carbon intensity. However, given the low partial pressure of CO in the flue stream, separation of CO is particularly challenging. Taking inspiration from the crystal structures of diamine-appended metal-organic frameworks exhibiting two-step cooperative CO adsorption, we report a family of robust tetraamine-functionalized frameworks that retain cooperativity, leading to the potential for exceptional efficiency in capturing CO under the extreme conditions relevant to natural gas flue emissions. The ordered, multimetal coordination of the tetraamines imparts the materials with extraordinary stability to adsorption-desorption cycling with simulated humid flue gas and enables regeneration using low-temperature steam in lieu of costly pressure or temperature swings.
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http://dx.doi.org/10.1126/science.abb3976DOI Listing
July 2020

Pancreaticoduodenectomy for the treatment of pancreatic neoplasms in children: A Pediatric Surgical Oncology Research Collaborative study.

Pediatr Blood Cancer 2020 09 13;67(9):e28425. Epub 2020 Jul 13.

Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.

Background: To better characterize short-term and long-term outcomes in children with pancreatic tumors treated with pancreaticoduodenectomy (PD).

Methods: Patients 21 years of age or younger who underwent PD at Pediatric Surgical Oncology Collaborative (PSORC) hospitals between 1990 and 2017 were identified. Demographic, clinical information, and outcomes (operative complications, long-term pancreatic function, recurrence, and survival) were collected.

Results: Sixty-five patients from 18 institutions with a median age of 13 years (4 months-22 years) and a median (IQR) follow-up of 2.8 (4.3) years were analyzed. Solid pseudopapillary tumor of the pancreas (SPN) was the most common histology. Postoperative complications included pancreatic leak in 14% (n = 9), delayed gastric emptying in 9% (n = 6), marginal ulcer in one patient, and perioperative (30-day) death due to hepatic failure in one patient. Pancreatic insufficiency was observed in 32% (n = 21) of patients, with 23%, 3%, and 6% with exocrine, or endocrine insufficiencies, or both, respectively. Children with SPN and benign neoplasms all survived. Overall, there were 14 (22%) recurrences and 11 deaths (17%). Univariate analysis revealed non-SPN malignant tumor diagnosis, preoperative vascular involvement, intraoperative transfusion requirement, pathologic vascular invasion, positive margins, and need for neoadjuvant chemotherapy as risk factors for recurrence and poor survival. Multivariate analysis only revealed pathologic vascular invasion as a risk factor for recurrence and poor survival.

Conclusion: This is the largest series of pediatric PD patients. PD is curative for SPN and benign neoplasms. Pancreatic insufficiency is the most common postoperative complication. Outcome is primarily associated with histology.
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http://dx.doi.org/10.1002/pbc.28425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674210PMC
September 2020

Bilateral Erector Spinae Plane (ESP) catheters for Ravitch procedure in a pediatric patient with Harrington rods.

J Clin Anesth 2020 Nov 2;66:109925. Epub 2020 Jun 2.

Division of Pain Medicine, Department of Anesthesiology Critical Care Medicine, Children's Hospital Los Angeles, United States of America.

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http://dx.doi.org/10.1016/j.jclinane.2020.109925DOI Listing
November 2020

Public Attitudes Toward Precision Medicine: A Nationwide Survey on Developing a National Cohort Program for Citizen Participation in the Republic of Korea.

Front Genet 2020 12;11:283. Epub 2020 May 12.

National Biobank of Korea, Center for Genome Science, Korea National Institute of Health, Cheonju-si, South Korea.

This nation-wide survey was conducted among Korean adults to examine the public interest in and attitudes toward establishing a citizen participation cohort model and to collect data to support and determine the future policy and research directions of the Resource Collection Project for Precision Medicine Research (RCP-PMR) before the project proceeds. The demographic framework of the survey population was established based on the statistical standards of the Ministry of the Interior and Safety. An online survey was carried out using web panels between 14 May 2018 and 23 May 2018. Sampling was performed using a simple proportional allocation method considering region, gender, and age. From this survey, the RCP-PMR received very high support (94.5%) and the intention to participate was as high as 83.5%. Respondents had a very positive attitude toward providing their samples and information to the study (84.5-89.9%). In terms of incentives to participate, respondents wanted to receive health information (80.2%), monetary compensation (51.4%), and smart devices (41.3%). Most participants responded that it was appropriate to carry out the project at governmental research institutes (66.9%). Respondents also had a positive attitude toward sharing their information and samples as long as it was only shared with the governmental researchers who run the project (88.0%). However, the survey participants expressed concerns about the study being time consuming or a hassle (38.1%), privacy breaches (33.6%), and the lack of returning benefits of participation (25.1%). Participants had a negative attitude toward sharing their data with researchers who are not directly involved in the RCP-PMR. Considering the future use of the database derived from this project, it will be important to communicate with the lay public as well as the RCP-PMR participants to understand their needs in participating in the forthcoming study and to improve their understanding of the goals of the project, and how data sharing can contribute to disease research and prevention. The RCP-PMR should consider building an efficient citizen-participation program and privacy protection for the research participants.
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http://dx.doi.org/10.3389/fgene.2020.00283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235362PMC
May 2020

Burden of Osteoporotic Fractures Using Disability-Adjusted Life Years in South Korea.

Asia Pac J Public Health 2020 Mar-Apr;32(2-3):111-117

Amgen Korea, Seoul, South Korea.

There is an increase in the number of patients with osteoporotic fractures due to the aging population in Korea. This study investigated the burden of osteoporotic fractures including hip, spine, and wrist fractures in the Korean population by estimating disability-adjusted life years (DALYs). The DALY for a given condition in a population captures years of life lost due to premature death and years of life lived with a disability and its severity and duration. To calculate DALYs from all relevant data collected for the 3 conditions, we used a DALY calculation template provided by the World Health Organization in 2014. DALYs per 100 000 for vertebral fractures (3168) were higher than those of hip fractures (2496) in women. Wrist fractures (1038) had the least burden, and the difference between men and women was the lowest. The aging population is expected to increase the burden of osteoporosis.
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http://dx.doi.org/10.1177/1010539520916376DOI Listing
July 2020