Publications by authors named "Sonia Sharma"

109 Publications

Aggregation-induced negative differential resistance in graphene oxide quantum dots.

Phys Chem Chem Phys 2021 Aug 1. Epub 2021 Aug 1.

Department of Physics and Center for Nanotechnology, Chung Yuan Christian University, Chung-Li, 320, Taiwan.

Negative differential resistance (NDR) devices have attracted considerable interest due to their potential applications in switches, memory devices, and analog-to-digital converters. Modulation of the NDR is an essential issue for the development of NDR-based devices. In this study, we successfully synthesized graphene oxide quantum dots (GOQDs) using graphene oxide, cysteine, and H2O2. The current-voltage characteristics of the GOQDs exhibit a clear NDR in the ambient environment at room temperature. A peak-to-valley ratio as high as 4.7 has been achieved under an applied voltage sweep from -6 to 6 V. The behavior of the NDR and its corresponding peak-to-valley ratio can be controlled by adjusting the range of applied voltages, air pressure, and relative humidity. Also, the NDR is sensitive to the the concentration of H2O2 added in the synthesis. The charge carrier injection through the trapping states, induced by the GOQD aggregation, could be responsible for the NDR behavior in GOQDs.
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http://dx.doi.org/10.1039/d1cp01529jDOI Listing
August 2021

Nontargeted mass spectrometry of dried blood spots for interrogation of the human circulating metabolome.

J Mass Spectrom 2021 May 27;56(8):e4772. Epub 2021 May 27.

Departments of Medicine and Pharmacology, University of California, San Diego, California, USA.

Advances in high-resolution, nontargeted mass spectrometry allow for the simultaneous measure of thousands of metabolites in a single biosample. Application of these analytical approaches to population-scale human studies has been limited by the need for resource-intensive blood sample collection, preparation, and storage. Dried blood spotting, a technique developed decades ago for newborn screening, may offer a simple approach to overcome barriers in human blood acquisition and storage. In this study, we find that over 4,400 spectral features across diverse chemical classes may be efficiently and reproducibly extracted and relatively quantified from human dried blood spots using nontargeted metabolomic analysis employing HILIC and reversed-phase liquid chromatography coupled to Orbitrap mass spectrometry. Moreover, over 80% of metabolites were found to be chemically stable in dried blood spots stored at room temperature for up to a week. In direct relation to plasma samples, dried blood spots exhibited comparable representation of the human circulating metabolome, capturing both known and previously uncharacterized metabolites. Dried blood spot approaches provide an opportunity for rapid and facile human biosampling and storage and will enable widespread metabolomics study of populations, particularly in resource-limited areas.
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http://dx.doi.org/10.1002/jms.4772DOI Listing
May 2021

Genome-wide CRISPR/Cas9 screening in human iPS derived cardiomyocytes uncovers novel mediators of doxorubicin cardiotoxicity.

Sci Rep 2021 Jul 6;11(1):13866. Epub 2021 Jul 6.

Department of Medicine, University of California, San Diego, San Diego, CA, USA.

Human induced pluripotent stem (iPS) cell technologies coupled with genetic engineering now facilitate the study of the molecular underpinnings of disease in relevant human cell types. Application of CRISPR/Cas9-based approaches for genome-scale functional screening in iPS-derived cells, however, has been limited by technical constraints, including inefficient transduction in pooled format, loss of library representation, and poor cellular differentiation. Herein, we present optimized approaches for whole-genome CRISPR/Cas9 based screening in human iPS derived cardiomyocytes with near genome-wide representation at both the iPS and differentiated cell stages. As proof-of-concept, we perform a screen to investigate mechanisms underlying doxorubicin mediated cell death in iPS derived cardiomyocytes. We identified two poorly characterized, human-specific transporters (SLCO1A2, SLCO1B3) whose loss of function protects against doxorubicin-cardiotoxicity, but does not affect cell death in cancer cells. This study provides a technical framework for genome-wide functional screening in iPS derived cells and identifies new targets to mitigate doxorubicin-cardiotoxicity in humans.
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http://dx.doi.org/10.1038/s41598-021-92988-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260754PMC
July 2021

Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease.

Genome Biol 2021 Jul 6;22(1):198. Epub 2021 Jul 6.

Oncode Institute, Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht, 3584, CT, Utrecht, the Netherlands.

Background: Recent studies highlight the role of metabolites in immune diseases, but it remains unknown how much of this effect is driven by genetic and non-genetic host factors.

Result: We systematically investigate circulating metabolites in a cohort of 500 healthy subjects (500FG) in whom immune function and activity are deeply measured and whose genetics are profiled. Our data reveal that several major metabolic pathways, including the alanine/glutamate pathway and the arachidonic acid pathway, have a strong impact on cytokine production in response to ex vivo stimulation. We also examine the genetic regulation of metabolites associated with immune phenotypes through genome-wide association analysis and identify 29 significant loci, including eight novel independent loci. Of these, one locus (rs174584-FADS2) associated with arachidonic acid metabolism is causally associated with Crohn's disease, suggesting it is a potential therapeutic target.

Conclusion: This study provides a comprehensive map of the integration between the blood metabolome and immune phenotypes, reveals novel genetic factors that regulate blood metabolite concentrations, and proposes an integrative approach for identifying new disease treatment targets.
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http://dx.doi.org/10.1186/s13059-021-02413-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259168PMC
July 2021

From Proteinuria to Fibrosis: An Update on Pathophysiology and Treatment Options.

Kidney Blood Press Res 2021 Jun 15:1-10. Epub 2021 Jun 15.

Department of Renal Medicine, St. George Hospital, Sydney, New South Wales, Australia.

Background: Proteinuria is a key biomarker in nephrology. It is central to diagnosis and risk assessment and the primary target of many important therapies. Etiologies resulting in pathological proteinuria include congenital and acquired disorders, as well as both glomerular (immune/non-immune mediated) and tubular defects.

Summary: Untreated proteinuria is strongly linked to progressive loss of kidney function and kidney failure. Excess protein reaching the renal tubules is ordinarily resorbed by the tubular epithelium. However, when these mechanisms are overwhelmed, a variety of inflammatory and fibrotic pathways are activated, causing both interstitial fibrosis and glomerulosclerosis. Nevertheless, the specific mechanisms underlying this are complex and remain incompletely understood. Recently, a number of treatments, in addition to angiotensin system blockade, have been shown to effectively slow the progression of proteinuric chronic kidney disease. However, additional therapies are clearly needed. Key message: This review provides an update on the pathophysiology of proteinuria, the pathways leading to fibrosis, and an overview of current and emerging therapies.
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http://dx.doi.org/10.1159/000516911DOI Listing
June 2021

Prevalence of Facial Pain and Headache in Sweden.

J Oral Facial Pain Headache 2021 Spring;35(2):139-149

Aims: To compare the prevalence of facial pain and headache across various regions in Sweden.

Methods: This study involved a comparison of cross-sectional questionnaire studies over a period of 10 years including 128,193 individuals and assessed facial pain, pain on function, and headache. Participants included (1) all Public Dental Service patients aged 16 to 90 years in Västerbotten (n = 57,283) and Gävleborg (n = 60,900); and (2) random samples of residents in Kalmar (n = 3,560) and Skåne (n = 6,450). Facial pain and pain on function were assessed for all participants, and headache was also assessed for participants in Kalmar and Skåne. Descriptive statistics were used to estimate unadjusted prevalence estimates and demographic characteristics. Prevalence estimates were adjusted for age and sex using weighted distributions from the 2015 data in the Swedish population registry before comparisons across the regions.

Results: Overall, the prevalence of facial pain and headache were significantly higher in female than in male participants (P < .01). The standardized prevalence of facial pain was 4.9% in Västerbotten, 1.4% in Gävleborg, 4.6% in Kalmar, and 7.6% in Skåne. For headache, the standardized prevalence was 18.9% in Kalmar and 21.3% in Skåne. In Skåne, individuals with facial pain had a 15-fold higher odds of headache than those without.

Conclusion: In the present Swedish epidemiologic study, the prevalence of facial pain ranged from 1.4% in Gävleborg to 7.6% in Skåne. Besides different sampling frames and other population characteristics, the presence of a high number of immigrants in Skåne may account for some differences in pain prevalence across the Swedish regions.
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http://dx.doi.org/10.11607/ofph.2645DOI Listing
June 2021

Adrenal Ganglioneuroma Presenting as an Incidentaloma in an Adolescent Patient.

AACE Clin Case Rep 2021 Jan-Feb;7(1):61-64. Epub 2020 Dec 28.

Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, Louisiana.

Objective: In an adult endocrine clinic, the majority of patients referred for evaluation of an incidentally discovered adrenal mass are aged more than 30 years, for which many national and international societies have developed management guidelines. However, adrenal incidentalomas in children and young adults are uncommon. We report the case of an 18-year-old woman with an incidentally discovered right-sided adrenal mass.

Methods: We present the adrenal tests, computed tomography, and magnetic resonance imaging results and treatment of a young woman with an adrenal mass that proved to be a ganglioneuroma.

Results: A computed tomography scan showed a 2.2 × 2.6 cm right-sided adrenal mass with noncontrast Hounsfield units >10 and <50% washout. Magnetic resonance imaging was not typical of a lipid-rich adenoma. Blood and urine tests demonstrated normal secretion of cortisol, aldosterone, adrenal androgens, and catecholamines. Based on the patient's age and imaging studies, she underwent a right adrenalectomy, removing a 2.2 × 2.0 × 2.7-cm ganglioneuroma.

Conclusion: The differential diagnosis of an adrenal mass in children and adolescents is quite different compared with adult patients. There are no standardized guidelines for the management of adrenal masses in these younger age groups, although some authors recommend removing all adrenal masses, regardless of size or imaging characteristics, in all children aged more than 3 months. This case emphasizes how the management of adrenal masses in pediatric patients and young adults differs from guidelines published by endocrine and urologic societies.
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http://dx.doi.org/10.1016/j.aace.2020.11.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924149PMC
December 2020

Diagnostic criteria for temporomandibular disorders (DC/TMD) for children and adolescents: An international Delphi study-Part 1-Development of Axis I.

J Oral Rehabil 2021 Jul 19;48(7):836-845. Epub 2021 May 19.

Department of Neurosciences, Reproductive Sciences and Oral Sciences, School of Orthodontics, University of Naples Federico II, Naples, Italy.

Background: Since in children and adolescence prevalence is assessed mainly on self-reported or proxy-reported signs and symptoms; there is a need to develop a more comprehensive standardised process for the collection of clinical information and the diagnosis of TMD in these populations.

Objective: To develop new instruments and to adapt the diagnostic criteria for temporomandibular disorders (DC/TMD) for the evaluation of TMD in children and adolescents.

Method: A modified Delphi method was used to seek international consensus among TMD experts. Fourteen clinicians and researchers in the field of oro-facial pain and TMD worldwide were invited to participate in a workshop initiated by the International Network for Orofacial Pain and Related Disorders Methodology (INfORM scientific network) at the General Session of the International Association for Dental Research (IADR, London 2018), as the first step in the Delphi process. Participants discussed the protocols required to make physical diagnoses included in the Axis I of the DC/TMD. Thereafter, nine experts in the field were added, and the first Delphi round was created. This survey included 60 statements for Axis I, and the experts were asked to respond to each statement on a five-item Likert scale ranging from 'Strongly disagree' to 'Strongly agree'. Consensus level was set at 80% agreement for the first round, and at 70% for the next.

Results: After three rounds of the Delphi process, a consensus among TMD experts was achieved and two adapted DC/TMD protocols for Axis I physical diagnoses for children and adolescents were developed.

Conclusion: Through international consensus among TMD experts, this study adapted the Axis I of the DC/TMD for use in evaluating TMD in children and adolescents.
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http://dx.doi.org/10.1111/joor.13175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252391PMC
July 2021

The tumor suppressor kinase DAPK3 drives tumor-intrinsic immunity through the STING-IFN-β pathway.

Nat Immunol 2021 04 25;22(4):485-496. Epub 2021 Mar 25.

La Jolla Institute for Immunology, La Jolla, CA, USA.

Evasion of host immunity is a hallmark of cancer; however, mechanisms linking oncogenic mutations and immune escape are incompletely understood. Through loss-of-function screening of 1,001 tumor suppressor genes, we identified death-associated protein kinase 3 (DAPK3) as a previously unrecognized driver of anti-tumor immunity through the stimulator of interferon genes (STING) pathway of cytosolic DNA sensing. Loss of DAPK3 expression or kinase activity impaired STING activation and interferon (IFN)-β-stimulated gene induction. DAPK3 deficiency in IFN-β-producing tumors drove rapid growth and reduced infiltration of CD103CD8α dendritic cells and cytotoxic lymphocytes, attenuating the response to cancer chemo-immunotherapy. Mechanistically, DAPK3 coordinated post-translational modification of STING. In unstimulated cells, DAPK3 inhibited STING K48-linked poly-ubiquitination and proteasome-mediated degradation. After cGAMP stimulation, DAPK3 was required for STING K63-linked poly-ubiquitination and STING-TANK-binding kinase 1 interaction. Comprehensive phospho-proteomics uncovered a DAPK3-specific phospho-site on the E3 ligase LMO7, critical for LMO7-STING interaction and STING K63-linked poly-ubiquitination. Thus, DAPK3 is an essential kinase for STING activation that drives tumor-intrinsic innate immunity and tumor immune surveillance.
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http://dx.doi.org/10.1038/s41590-021-00896-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300883PMC
April 2021

Total Synthesis and Conformational Analysis of Naturally Occurring Lipovelutibols along with Lead Optimization of Lipovelutibol D.

ACS Omega 2021 Mar 26;6(9):6070-6080. Epub 2021 Feb 26.

Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.

Four lipopeptaibols, namely, lipovelutibols A-D, were recently isolated from psychrotrophic fungus and reported to have significant cytotoxic activity against HL-60, MDA-MD-231, A549, and LS180 cancer cell lines. In the present study, these peptides were synthesized in a solution using a segment condensation approach. The conformational analysis of these peptides carried out using CD spectrophotometry revealed the formation of 3-helix, and the NMR-VT experiments showed intramolecular hydrogen bonding for NH-5, NH-6, and NH-7. Lipovelutibol D showed potent cytotoxic activity and was chosen for lead optimization. It involved N- and Cterminal truncation, N- and Cterminal modification, random deletion, l/d configuration replacement, and other synthetic analogues. These were tested against various breast cancer cell lines. The C-terminal aldehyde analogue resulting from lead optimization of lipovelutibol D was found to have almost twofold enhanced cytotoxicity against MDA-MB-231 breast cancer cell lines.
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http://dx.doi.org/10.1021/acsomega.0c04038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948224PMC
March 2021

Adynamic bone disease: Revisited.

Nefrologia (Engl Ed) 2021 Mar 8. Epub 2021 Mar 8.

Department of Medicine, Whakatane Hospital, Whakatane, New Zealand. Electronic address:

The bone and mineral disorders form an integral part of the management of a chronic kidney disease (CKD) patient. Amongst various types of bone pathologies in chronic kidney disease-mineral bone disorder (CKD-MBD), the prevalence of adynamic bone disease (ABD) is increasing. The present review discusses the updated pathophysiology, risk factors, and management of this disorder.
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http://dx.doi.org/10.1016/j.nefro.2020.11.012DOI Listing
March 2021

Seroprevalence of antibodies to SARS-CoV-2 in healthcare workers: a cross-sectional study.

BMJ Open 2021 02 12;11(2):e043584. Epub 2021 Feb 12.

Center for Neural Science and Medicine, Department of Biomedical Sciences, Board of Governors Regenerative Medicine Institute, Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Objective: We sought to determine the extent of SARS-CoV-2 seroprevalence and the factors associated with seroprevalence across a diverse cohort of healthcare workers.

Design: Observational cohort study of healthcare workers, including SARS-CoV-2 serology testing and participant questionnaires.

Settings: A multisite healthcare delivery system located in Los Angeles County.

Participants: A diverse and unselected population of adults (n=6062) employed in a multisite healthcare delivery system located in Los Angeles County, including individuals with direct patient contact and others with non-patient-oriented work functions.

Main Outcomes: Using Bayesian and multivariate analyses, we estimated seroprevalence and factors associated with seropositivity and antibody levels, including pre-existing demographic and clinical characteristics; potential COVID-19 illness-related exposures; and symptoms consistent with COVID-19 infection.

Results: We observed a seroprevalence rate of 4.1%, with anosmia as the most prominently associated self-reported symptom (OR 11.04, p<0.001) in addition to fever (OR 2.02, p=0.002) and myalgias (OR 1.65, p=0.035). After adjusting for potential confounders, seroprevalence was also associated with Hispanic ethnicity (OR 1.98, p=0.001) and African-American race (OR 2.02, p=0.027) as well as contact with a COVID-19-diagnosed individual in the household (OR 5.73, p<0.001) or clinical work setting (OR 1.76, p=0.002). Importantly, African-American race and Hispanic ethnicity were associated with antibody positivity even after adjusting for personal COVID-19 diagnosis status, suggesting the contribution of unmeasured structural or societal factors.

Conclusion And Relevance: The demographic factors associated with SARS-CoV-2 seroprevalence among our healthcare workers underscore the importance of exposure sources beyond the workplace. The size and diversity of our study population, combined with robust survey and modelling techniques, provide a vibrant picture of the demographic factors, exposures and symptoms that can identify individuals with susceptibility as well as potential to mount an immune response to COVID-19.
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http://dx.doi.org/10.1136/bmjopen-2020-043584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883610PMC
February 2021

Functional Analysis of Immune Signature Genes in Th1* Memory Cells Links ISOC1 and Pyrimidine Metabolism to IFN-γ and IL-17 Production.

J Immunol 2021 03 5;206(6):1181-1193. Epub 2021 Feb 5.

La Jolla Institute for Immunology, La Jolla, CA 92037;

CCR6CXCR3CCR4CD4 memory T cells, termed Th1*, are important for long-term immunity to and the pathogenesis of autoimmune diseases. Th1* cells express a unique set of lineage-specific transcription factors characteristic of both Th1 and Th17 cells and display distinct gene expression profiles compared with other CD4 T cell subsets. To examine molecules and signaling pathways important for the effector function of Th1* cells, we performed loss-of-function screening of genes selectively enriched in the Th1* subset. The genetic screen yielded candidates whose depletion significantly impaired TCR-induced IFN-γ production. These included genes previously linked to IFN-γ or susceptibility and novel candidates, such as , encoding a metabolic enzyme of unknown function in mammalian cells. ISOC1-depleted T cells, which produced less IFN-γ and IL-17, displayed defects in oxidative phosphorylation and glycolysis and impairment of pyrimidine metabolic pathway. Supplementation with extracellular pyrimidines rescued both bioenergetics and IFN-γ production in ISOC1-deficient T cells, indicating that pyrimidine metabolism is a key driver of effector functions in CD4 T cells and Th1* cells. Results provide new insights into the immune-stimulatory function of ISOC1 as well as the particular metabolic requirements of human memory T cells, providing a novel resource for understanding long-term T cell-driven responses.
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http://dx.doi.org/10.4049/jimmunol.2000672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946769PMC
March 2021

Erratum: Long-term outcome in inherited nephrogenic diabetes insipidus.

Clin Kidney J 2020 Dec 7;13(6):1111. Epub 2020 Dec 7.

[This corrects the article DOI: 10.1093/ckj/sfy027.][This corrects the article DOI: 10.1093/ckj/sfy027.].
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http://dx.doi.org/10.1093/ckj/sfaa223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769540PMC
December 2020

Comparative analytical profiling of bevacizumab biosimilars marketed in India: a national control laboratory study.

3 Biotech 2020 Dec 9;10(12):516. Epub 2020 Nov 9.

National Institute of Biologicals, (Ministry of Health and Family Welfare, Govt. of India), A-32, Sector 62, Noida, 201309 India.

In this study, analytical profiling of the bevacizumab (BVZ) biosimilars ( = 3) approved in India were evaluated for charge heterogeneity, isoelectric focusing, aggregation and in vitro potency analysis. The charge variants were characterized using high performance cation-exchange chromatography (CEX-HPLC), capillary zone electrophoresis (CZE) and capillary isoelectric focusing (cIEF). cIEF was also used for estimation of isoelectric point (pI value). In addition, aggregate analysis was done using size exclusion high performance chromatography (SEC-HPLC). The cell-based inhibition of proliferation assay using HUVEC cells, indirect ELISA and Western blot were performed for in vitro biological activity. In addition of cell-based cytotoxicity assay was also performed and found no cytotoxic effect on both HuT78 and WIL2S cells by bevacizumab biosimilars. The significant variations in acidic ( < 0.0001) and basic variants ( < 0.0001), pI value ( = 0.0035), aggregates ( = 0.0306) of biosimilars were found as compared to innovator product; however, cell-based potency analysis ( = 0.6047) and indirect ELISA ( = 0.1611) have shown no significant difference in the biological activity. The banding patterns of all biosimilars in western blot were found similar to the innovator product. The comparatively higher basic variants in the biosimilars were attributing to the high pI value of biosimilars to that of innovator product, although these variations were not affecting the biological activity of the biosimiars. This is a unique study, wherein the independent analysis by a National Control Laboratory (NCL) will not only help the National Regulatory Authority (NRA) to assess the quality and consistency in manufacturing of BVZ biosimilars marketed in India but also facilitate the uptake of BVZ biosimilars, and sustainable access to new medicines against the anti-angiogenic therapy.
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http://dx.doi.org/10.1007/s13205-020-02506-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652956PMC
December 2020

Orofacial pain education in dentistry: A path to improving patient care and reducing the population burden of chronic pain.

J Dent Educ 2021 Mar 23;85(3):349-358. Epub 2020 Oct 23.

Department of Geriatric Dentistry, Osaka Dental University, Osaka, Japan.

Dentists stand in an optimal position to prevent and manage patients suffering from chronic orofacial pain (OFP) disorders, such as temporomandibular disorders, burning mouth syndrome, trigeminal neuralgia, persistent idiopathic dentoalveolar pain, among others. However, there are consistent reports highlighting a lack of knowledge and confidence in diagnosing and treating OFP among dental students, recent graduates, and trained dentists, which leads to misdiagnosis, unnecessary costs, delay in appropriate care and possible harm to patients. Education in OFP is necessary to improve the quality of general dental care and reduce individual and societal burden of chronic pain through prevention and improved quality of life for OFP patients. Our aims are to emphasize the goals of OFP education, to identify barriers for its implementation, and to suggest possible avenues to improve OFP education in general, postgraduate, and continuing dental education levels, including proposed minimum OFP competencies for all dentists. Moreover, patient perspectives are also incorporated, including a testimony from a person with OFP. General dentists, OFP experts, educators, researchers, patients, and policy makers need to combine efforts in order to successfully address the urgent need for quality OFP education.
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http://dx.doi.org/10.1002/jdd.12461DOI Listing
March 2021

Attributes Germane to Temporomandibular Disorders and Their Associations with Five Chronic Overlapping Pain Conditions.

J Oral Facial Pain Headache 2020 Suppl;34:s57-s72

Aims: To investigate whether TMD-related characteristics are indeed specific to TMD or whether they are also associated with other chronic overlapping pain conditions (COPCs).

Methods: In this cross-sectional study, 22 characteristics related broadly to TMD (eg, jaw kinesiophobia, overuse behaviors, and functional limitation) were measured in 178 painful TMD cases who were also classified according to four COPCs: headache, low back pain, irritable bowel syndrome, and fibromyalgia. Differences in mean subscale scores were compared according to individual chronic pain conditions and according to number of COPCs.

Results: Headache, low back pain, irritable bowel syndrome, and fibromyalgia were each associated (P < .05) with higher values of at least one TMD-relevant characteristic. In the multivariable analysis, TMD was independently associated with 20 of the 22 characteristics (P < .01), and other COPCs were associated variably. A critical threshold existed between the number of COPCs and TMD characteristics: all characteristics were elevated for subjects with ≥ 3 COPCs (P ≤ .01).

Conclusion: The overlap between COPCs and characteristics typically regarded as specific to painful TMD has implications for treatment targeted at both the local TMD condition and the broader pain disorder underlying the COPC(s). In TMD patients, the overall burden of pain from COPCs may create a shift in the pain-processing systems that underlie these TMD-relevant characteristics.
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http://dx.doi.org/10.11607/ofph.2582DOI Listing
September 2020

Clinical Characteristics of Pain Among Five Chronic Overlapping Pain Conditions.

J Oral Facial Pain Headache 2020 Suppl;34:s29-s42

Aims: To describe the pain characteristics of five index chronic overlapping pain conditions (COPCs) and to assess each COPC separately in order to determine whether the presence of comorbid COPCs is associated with bodily pain distribution, pain intensity, pain interference, and high-impact pain of the index COPC.

Methods: Data were from a convenience sample of 655 US adults, of whom 388 had one or more of the five COPCs: painful temporomandibular disorders, headache, low back pain, irritable bowel syndrome, and/or fibromyalgia. Data were collected using pain location checklists and self-report questions regarding pain attributes. The contributions of the COPCs to reported pain intensity and interference were assessed using multivariable regression models.

Results/conclusion: Heat maps from a pain body manikin illustrated that very little of the body was pain free within these COPCs. All pain attributes were the most severe for fibromyalgia and the least severe for irritable bowel syndrome. Within each index COPC, pain intensity, pain interference, and the proportion of participants with high-impact pain increased with each additional comorbid COPC up to four or more COPCs (including the index COPC) (P < .01). High-impact pain associated with an index COPC was influenced by type and number of comorbid COPCs, largely in a gradient-specific manner.
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http://dx.doi.org/10.11607/ofph.2573DOI Listing
September 2020

Overlap of Five Chronic Pain Conditions: Temporomandibular Disorders, Headache, Back Pain, Irritable Bowel Syndrome, and Fibromyalgia.

J Oral Facial Pain Headache 2020 Suppl;34:s15-s28

Aims: To assess cohort retention in the OPPERA project and to compare the degree of overlap between pairs of chronic overlapping pain conditions (COPCs) using a cross-sectional analysis of data from 655 adults who completed follow-up in the OPPERA study.

Methods: Subjects were classified for the absence or presence of each of the five COPCs. The extent of overlap beyond chance was quantified using odds ratios, which were calculated using binary logistic regression models.

Results: While overlap was the norm, its magnitude varied according to COPC: 51% of people with headache had one or more overlapping COPCs, and this proportion increased to 90% for people with fibromyalgia. The degree of overlap between pairs of COPCs also varied considerably, with odds ratios being greatest for associations between musculoskeletal conditions (fibromyalgia, temporomandibular disorders, and low back pain) and less pronounced for overlap involving headache or IBS. Furthermore, univariate associations between some pairs of COPCs were nullified after adjusting for other COPCs.

Conclusion: There was greater overlap between fibromyalgia and either temporomandibular disorders or low back pain than between other pairs of COPCs. While musculoskeletal conditions exhibited some features that could be explained by a single functional syndrome, headache and irritable bowel syndrome did not.
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http://dx.doi.org/10.11607/ofph.2581DOI Listing
September 2020

Cellular sensing of extracellular purine nucleosides triggers an innate IFN-β response.

Sci Adv 2020 Jul 22;6(30):eaba3688. Epub 2020 Jul 22.

La Jolla Institute for Immunology, La Jolla, CA 92037, USA.

Mechanisms linking immune sensing of DNA danger signals in the extracellular environment to innate pathways in the cytosol are poorly understood. Here, we identify a previously unidentified immune-metabolic axis by which cells respond to purine nucleosides and trigger a type I interferon-β (IFN-β) response. We find that depletion of ADA2, an ectoenzyme that catabolizes extracellular dAdo to dIno, or supplementation of dAdo or dIno stimulates IFN-β. Under conditions of reduced ADA2 enzyme activity, dAdo is transported into cells and undergoes catabolysis by the cytosolic isoenzyme ADA1, driving intracellular accumulation of dIno. dIno is a functional immunometabolite that interferes with the cellular methionine cycle by inhibiting SAM synthetase activity. Inhibition of SAM-dependent transmethylation drives epigenomic hypomethylation and overexpression of immune-stimulatory endogenous retroviral elements that engage cytosolic dsRNA sensors and induce IFN-β. We uncovered a previously unknown cellular signaling pathway that responds to extracellular DNA-derived metabolites, coupling nucleoside catabolism by adenosine deaminases to cellular IFN-β production.
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http://dx.doi.org/10.1126/sciadv.aba3688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375821PMC
July 2020

A Clinical Update on Childhood Hypertension.

Pediatr Endocrinol Rev 2020 Jun;17(3):250-256

RG Stone Hospital, Pitumpura, New Delhi, India.

Background: Hypertension is one of the leading morbid factors in adults but often a less noticeable concern in childhood age group. Young population is now more vulnerable to lifestyle disorders leading to early chronic diseases if not addressed due to presence of ignorance and inadequate assessment. To label hypertension in pediatric age group, blood pressure should be ≥ 95th percentile for age, height and sex in small children.

Objective: Purpose of review is to unfurl the knowledge for monitoring and management of hypertension in children. We emphasize the need to spread awareness in community, especially in rural areas of low and middle economy nations, which is surely lacking despite available tools for more then 60-70 years.

Outcome: Comprehensive clinical update on recent information on epidemiology, the diagnosis, evaluation and management of pediatric hypertension for outpatient clinic practice.
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http://dx.doi.org/10.17458/per.vol17.2020.shsh.clinicalchildhoodhypertensionDOI Listing
June 2020

Failure to Thrive, Jaundice, and Polyuria in Early Infancy: Common Presentation with an Uncommon Lethal Etiology.

Authors:
Sonia Sharma

J Pediatr Genet 2020 Sep 11;9(3):183-185. Epub 2019 Nov 11.

Pediatric Nephrology Unit, Department of Pediatrics, Max Super Speciality Hospital, New Delhi, India.

A 5-month-old female infant from a consanguineous Indian Muslim family presented with polyuria, polydipsia, failure to thrive, impaired renal function, and neonatal hepatitis of unknown cause at 1 month of age. Clinical exome testing revealed renal-hepatic-pancreatic dysplasia caused by homozygous c. 1985 + 5G > A pathogenic variations in . Our case illustrates delay in confirmatory diagnosis of such rare disorders in our region due to the lack of suspicion and unawareness of the availability of genetic testing even when there are no cost constraints.
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http://dx.doi.org/10.1055/s-0039-1700802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375847PMC
September 2020

Biocontrol potential of chitinases produced by newly isolated Chitinophaga sp. S167.

World J Microbiol Biotechnol 2020 Jun 11;36(6):90. Epub 2020 Jun 11.

Department cum National Centre for Human Genome Studies and Research, Panjab University, Chandigarh, India.

A chitinolytic bacterium Chitinophaga sp. S167 producing extracellular chitinases was isolated from a soil sample in India. The extracellular chitinases produced by S167 were concentrated by ammonium sulphate precipitation (AS70) and seven bands corresponding to chitinases were observed by zymography. Optimum temperature and pH of AS70 were between 40 and 45 °C and pH 6.0 respectively with high stability at 20-40 °C and pH 5-7. AS70 inhibited the growth of Fusarium oxysporum, Alternaria alternata and Cladosporium sp. in vitro. The culture conditions for the high level production of extracellular chitinases were optimized resulting in 48-folds higher chitinase production. As the combination of chitinases could be more potent in biocontrol of plant diseases, it was checked if AS70 could control postharvest fungal infection caused by Fusarium oxysporum on tomatoes. AS70 treated tomatoes showed significant lower incidence of infection (11%) by F. oxysporum as compared with 100% in the control at 5 days post inoculation. Further, AS70 caused significant mortality in second stage juveniles of root knot nematode, Meloidogyne incognita, a major agriculture pest responsible for economic losses in agriculture. This study highlights the antifungal and nematicidal activity of chitinases produced by Chitinophaga sp. S167. To the best of our knowledge, this is the first report of the biocontrol potential of the chitinases produced by Chitinophaga sp.
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http://dx.doi.org/10.1007/s11274-020-02864-9DOI Listing
June 2020

In Silico Characterization of a Unique Plant-Like "Loopful" GH19 Chitinase from Newly Isolated Chitinophaga sp. YS-16.

Curr Microbiol 2020 Sep 14;77(9):2248-2257. Epub 2020 May 14.

Department Cum National Centre for Human Genome Studies and Research, Panjab University, Chandigarh, India.

Chitinases are glycohydrolases that cleave β-1,4 linkages in chitin and are grouped into glycohydrolase (GH) family 18 and 19. GH18 chitinases are found ubiquitously, whereas GH19 chitinases are confined predominantly to higher plants and few bacteria. In this study, a new chitinolytic bacterium, Chitinophaga sp. YS-16, was isolated and identified as a close relative of Chitinophaga pinensis DSM 2588 with 99.41% similarity of 16S rRNA sequence. The gene encoding for GH19 chitinase bearing unique domain architecture was amplified from the genomic DNA of YS-16. The sequence of GH19 chitinase (CpChi) encoded in the genome of YS-16 showed 90.5% identity with the sequence of GH19 chitinase encoded in genome of C. pinensis DSM 2588 (ACU62980.1). Bioinformatics analyses of CpChi revealed it to be a 'loopful' chitinase which has been reported only from plants till date. The tertiary structure of the catalytic domain of CpChi (CtCpChi) was predicted by homology modelling. The docking of modelled structure of CtCpChi with oligomers of N-acetyl-D-glucosamine (GlcNAc) revealed that the binding cleft of CtCpChi could accommodate an octamer of GlcNAc, not known in any other reported bacterial chitinase. Phylogenetic analysis supports CtCpChi to be plant-like GH19 chitinase.
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http://dx.doi.org/10.1007/s00284-020-02022-2DOI Listing
September 2020

Human resources and curricula content for early child development implementation: multicountry mixed methods evaluation.

BMJ Open 2020 04 26;10(4):e032134. Epub 2020 Apr 26.

Maternal, Adolescent, Reproductive and Child Health Centre, London School of Hygiene and Tropical Medicine, London, UK

Objective: The WHO recommends responsive caregiving and early learning (RCEL) interventions to improve early child development (ECD), and to achieve the Sustainable Development Goals' vision of a world where all children thrive. Implementation of RCEL programmes in low and middle-income countries (LMIC) requires evidence to inform decisions about human resources and curricula content. We aimed to describe human resources and curricula content for implementation of RCEL projects across diverse LMICs, using data from the Grand Challenges Canada Saving Brains ECD portfolio.

Setting: We evaluated 32 RCEL projects across 17 LMICs on four continents.

Participants: Overall, 2165 workers delivered ECD interventions to 25 909 families.

Intervention: Projects were either stand-alone RCEL or RCEL combined with health and nutrition, and/or safety and security.

Primary And Secondary Outcomes: We undertook a mixed methods evaluation of RCEL projects within the Saving Brains portfolio. Quantitative data were collected through standardised reporting tools. Qualitative data were collected from ECD experts and stakeholders and analysed using thematic content analysis, informed by literature review.

Results: Major themes regarding human resources included: worker characteristics, incentivisation, retention, training and supervision, and regarding curricula content: flexible adaptation of content and delivery, fidelity, and intervention duration and dosage. Lack of an agreed standard ECD package contributed to project heterogeneity. Incorporation of ECD into existing services may facilitate scale-up but overburdened workers plus potential reductions in service quality remain challenging. Supportive training and supervision, inducement, worker retention, dosage and delivery modality emerged as key implementation decisions.

Conclusions: This mixed methods evaluation of a multicountry ECD portfolio identified themes for consideration by policymakers and programme leaders relevant to RCEL implementation in diverse LMICs. Larger studies, which also examine impact, including high-quality process and costing evaluations with comparable data, are required to further inform decisions for implementation of RCEL projects at national and regional scales.
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http://dx.doi.org/10.1136/bmjopen-2019-032134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204990PMC
April 2020

Parathyroidectomy in First Trimester of Pregnancy.

J Endocr Soc 2020 Mar 5;4(3):bvaa015. Epub 2020 Feb 5.

Department of Otolaryngology-Head and Neck Surgery, Louisiana State University Health Sciences Center, Shreveport, Louisiana.

Primary hyperparathyroidism is not commonly diagnosed during pregnancy. For pregnant women with mild, asymptomatic disease, surgery can be avoided unless the degree of hypercalcemia becomes more severe or they develop complications. However, there are no evidence-based guidelines to assist clinicians regarding the management of primary hyperparathyroidism during pregnancy. When surgery is deemed necessary during pregnancy, the second trimester is generally considered to be the optimal time. We report the case of a 31-year-old female G1P0 who presented at 6 weeks gestation with symptoms of nausea, vomiting, polyuria, and corrected calcium of 14.8 mg/dL. Due to the extreme degree of hypercalcemia and refractory to medical treatment, it was decided that surgery could not be delayed until the second trimester. At 7w3d gestational age the patient had resection of a 37 gram, 5 × 4 × 3 cm right inferior parathyroid adenoma.
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http://dx.doi.org/10.1210/jendso/bvaa015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049289PMC
March 2020

Identification of Lineage-Specific Transcription Factors That Prevent Activation of Hepatic Stellate Cells and Promote Fibrosis Resolution.

Gastroenterology 2020 05 23;158(6):1728-1744.e14. Epub 2020 Jan 23.

Department of Surgery, University of California San Diego, La Jolla, California. Electronic address:

Background & Aims: Development of liver fibrosis is associated with activation of quiescent hepatic stellate cells (HSCs) into collagen type I-producing myofibroblasts (activated HSCs). Cessation of liver injury often results in fibrosis resolution and inactivation of activated HSCs/myofibroblasts into a quiescent-like state (inactivated HSCs). We aimed to identify molecular features of phenotypes of HSCs from mice and humans.

Methods: We performed studies with Lrat, Ets1-floxed, Nf1-floxed, Pparγ-floxed, Gata6-floxed, Rag2γc, and C57/Bl6 (control) mice. Some mice were given carbon tetrachloride (CCl) to induce liver fibrosis, with or without a peroxisome proliferator-activated receptor-γ (PPARγ) agonist. Livers from mice were analyzed by immunohistochemistry. Quiescent, activated, and inactivated HSCs were isolated from livers of Col1α1 mice and analyzed by chromatin immunoprecipitation and sequencing. Human HSCs were isolated from livers denied for transplantation. We compared changes in gene expression patterns and epigenetic modifications (histone H3 lysine 4 dimethylation and histone H3 lysine 27 acetylation) in primary mouse and human HSCs. Transcription factors were knocked down with small hairpin RNAs in mouse HSCs.

Results: Motif enrichment identified E26 transcription-specific transcription factors (ETS) 1, ETS2, GATA4, GATA6, interferon regulatory factor (IRF) 1, and IRF2 transcription factors as regulators of the mouse and human HSC lineage. Small hairpin RNA-knockdown of these transcription factors resulted in increased expression of genes that promote fibrogenesis and inflammation, and loss of HSC phenotype. Disruption of Gata6 or Ets1, or Nf1 or Pparγ (which are regulated by ETS1), increased the severity of CCl-induced liver fibrosis in mice compared to control mice. Only mice with disruption of Gata6 or Pparγ had defects in fibrosis resolution after CCl administration was stopped, associated with persistent activation of HSCs. Administration of a PPARγ agonist accelerated regression of liver fibrosis after CCl administration in control mice but not in mice with disruption of Pparγ.

Conclusions: Phenotypes of HSCs from humans and mice are regulated by transcription factors, including ETS1, ETS2, GATA4, GATA6, IRF1, and IRF2. Activated mouse and human HSCs can revert to a quiescent-like, inactivated phenotype. We found GATA6 and PPARγ to be required for inactivation of human HSCs and regression of liver fibrosis in mice.
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http://dx.doi.org/10.1053/j.gastro.2020.01.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252905PMC
May 2020

Zika Virus Targets Glioblastoma Stem Cells through a SOX2-Integrin αβ Axis.

Cell Stem Cell 2020 02 16;26(2):187-204.e10. Epub 2020 Jan 16.

Department of Anesthesiology, Center for the Study of Itch, Washington University School of Medicine in St. Louis, St. Louis, MO 63130, USA.

Zika virus (ZIKV) causes microcephaly by killing neural precursor cells (NPCs) and other brain cells. ZIKV also displays therapeutic oncolytic activity against glioblastoma (GBM) stem cells (GSCs). Here we demonstrate that ZIKV preferentially infected and killed GSCs and stem-like cells in medulloblastoma and ependymoma in a SOX2-dependent manner. Targeting SOX2 severely attenuated ZIKV infection, in contrast to AXL. As mechanisms of SOX2-mediated ZIKV infection, we identified inverse expression of antiviral interferon response genes (ISGs) and positive correlation with integrin α (ITGAV). ZIKV infection was disrupted by genetic targeting of ITGAV or its binding partner ITGB5 and by an antibody specific for integrin αβ. ZIKV selectively eliminated GSCs from species-matched human mature cerebral organoids and GBM surgical specimens, which was reversed by integrin αβ inhibition. Collectively, our studies identify integrin αβ as a functional cancer stem cell marker essential for GBM maintenance and ZIKV infection, providing potential brain tumor therapy.
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http://dx.doi.org/10.1016/j.stem.2019.11.016DOI Listing
February 2020

Predisposing Factors, Ophthalmic Manifestations, and Radiological Findings in Children With Cerebral Visual Impairment.

J Pediatr Ophthalmol Strabismus 2019 Sep;56(5):313-318

Purpose: To describe predisposing factors, ophthalmic manifestations, and magnetic resonance imaging (MRI) findings in children with cerebral visual impairment.

Methods: A retrospective cross-sectional analysis of patients younger than 16 years with neuroradiological and clinical evidence of retrogeniculate visual pathway pathology was performed. Detailed histories, ophthalmic examinations, and MRI findings were compiled and analyzed.

Results: Of the 88 cases included in the study, the median age was 32 months (range: 1 to 180 months). Ante-natal history and preterm delivery was positive in 25.0% and 37.5% of patients, respectively. A simple myopic astigmatism was the most common refractive error. Accommodative anomalies were noted in 6 children.

Conclusions: The demographic trends found in the study were similar to those of developed nations, but the frequency of the predisposing factors varied. A comprehensive knowledge of cerebral visual impairment in the developing world can aid an earlier diagnosis, appropriate management, and the development of better rehabilitation teams. [J Pediatr Ophthalmol Strabismus. 2019;56(5):313-318.].
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http://dx.doi.org/10.3928/01913913-20190610-01DOI Listing
September 2019
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