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Author: David Mowat (67)


Jan
2018

Unhealthy foods are widely available in public settings across Canada, contributing to diet-related chronic diseases, such as obesity. This is a concern given that public facilities often provide a significant amount of food for consumption by vulnerable groups, including children and seniors. Healthy food procurement policies, which support procuring, distributing, selling, and/or serving healthier foods, have recently emerged as a promising strategy to counter this public health issue by increasing access to healthier foods.

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Jan
2018

Epileptic encephalopathies are a devastating group of neurological conditions in which etiological diagnosis can alter management and clinical outcome. Exome sequencing and gene panel testing can improve diagnostic yield but there is no cost-effectiveness analysis of their use or consensus on how to best integrate these tests into clinical diagnostic pathways.
We conducted a retrospective cost-effectiveness study comparing trio exome sequencing with a standard diagnostic approach, for a well-phenotyped cohort of 32 patients with epileptic encephalopathy, who remained undiagnosed after "first-tier" testing.

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Dec
2017

Non-syndromic congenital hydrocephalus is aetiologically diverse and while a genetic cause is frequently suspected, it often cannot be confirmed. The most common genetic cause is L1CAM-related X-linked hydrocephalus and that explains only 5%-10% of all male cases. This underlines a current limitation in our understanding of the genetic burden of non-syndromic congenital hydrocephalus, especially for those cases with likely autosomal recessive inheritance.

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Dec
2017

PurposeThe craniosynostoses are characterized by premature fusion of one or more cranial sutures. The relative contribution of previously reported genes to craniosynostosis in large cohorts is unclear. Here we report on the use of a massively parallel sequencing panel in individuals with craniosynostosis without a prior molecular diagnosis.

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Dec
2017

Tuberous sclerosis complex (TSC) is an auto-somal-dominant inherited condition with an incidence of approximately 1:6000 births, characterised by deregulated mTOR activity with multi-site hamartomas. Subependymal giant cell astrocytomas (SEGA) are one such hamartoma, affecting up to 24% of patients with TSC. Their intraventricular location may lead to life-threatening obstructive hydrocephalus.

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Nov
2017

Tuberous sclerosis complex (TSC) is an autosomal dominant condition associated with epilepsy, benign tumors, and variable neurodevelopmental outcomes. The diagnosis is most commonly made after epilepsy onset, although a proportion are diagnosed prenatally. Presymptomatic or early treatment with agents such as vigabatrin offers the hope of improved neurodevelopmental outcome.

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Dec
1969

Paediatric motor neuron diseases encompass a group of neurodegenerative diseases characterised by the onset of muscle weakness and atrophy before the age of 18 years, attributable to motor neuron loss across various neuronal networks in the brain and spinal cord. While the genetic underpinnings are diverse, advances in next generation sequencing have transformed diagnostic paradigms. This has reinforced the clinical phenotyping and molecular genetic expertise required to navigate the complexities of such diagnoses.

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Jun
2017

The Canadian Partnership Against Cancer funded 12 large-scale knowledge to action cancer and chronic disease prevention projects between 2009 and 2016 through the Coalitions Linking Action and Science for Prevention (CLASP) initiative. Two projects, Healthy Canada by Design (HCBD) and Children's Mobility, Health and Happiness (CMHH), developed policies to address physical activity and the built environment through a multisectoral approach. A qualitative analysis involving a review of 183 knowledge products and 8 key informant interviews was conducted to understand what policy changes occurred, and the underlying critical success factors, through these projects.

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May
2017

Alveolar capillary dysplasia (ACD) is a rare condition with variable presentation and clinical course. Clinicians should consider this diagnosis in neonates presenting with nonlethal congenital gastrointestinal malformation, a period of well-being after birth then unremitting hypoxemia and refractory pulmonary hypertension. Lung biopsy andgene testing may help in diagnosis.

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Mar
2017

Mowat-Wilson Syndrome (MWS) is caused by deletion/mutation of the ZEB2 gene on chromosome 2q22. MWS is characterized by a distinctive facial appearance, severe intellectual disability and other anomalies, e.g.

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Dec
1969

Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously.

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Oct
2016

Survival of motor neuron 1-------negative spinal muscular atrophy (SMA) is heterogeneous and remains a diagnostic challenge. The clinical spectrum continues to expand and ∼33 genes have been identified to date. The present report describes a 9-year-old girl with novel clinical phenotype of a patient with polyarticular arthritis followed by symptoms of SMA due to acid ceramidase deficiency.

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Dec
1969

With the advent of whole exome sequencing, cases where no pathogenic coding mutations can be found are increasingly being observed in many diseases. In two large, distantly-related families that mapped to the Charcot-Marie-Tooth neuropathy CMTX3 locus at chromosome Xq26.3-q27.

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Feb
2016

Early Infantile Epileptic Encephalopathy (EIEE) presents shortly after birth with frequent, severe seizures, a burst-suppression EEG pattern, and progressive disturbance of cerebral function. We present a case of EIEE associated with a de novo missense variant in ZEB2. Heterozygous truncating mutations or deletions in ZEB2 are known to cause Mowat-Wilson syndrome (MWS), which is characterized by seizures with onset in the second year of life, distinctive dysmorphic facial features and malformations that were absent in this patient.

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Apr
2016

Congenital cataracts are a significant cause of lifelong visual loss. They may be isolated or associated with microcornea, microphthalmia, anterior segment dysgenesis (ASD) and glaucoma, and there can be syndromic associations. Genetic diagnosis is challenging due to marked genetic heterogeneity.

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Mar
2016

Sleep disturbance in Mowat-Wilson syndrome.

Am J Med Genet A 2016 Mar 21;170(3):654-60. Epub 2015 Dec 21.
Elizabeth Evans, David Mowat, Meredith Wilson, Stewart Einfeld
Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome caused by a heterozygous mutation or deletion of the ZEB2 gene. It is characterized by a distinctive facial appearance in association with intellectual disability (ID) and variable other features including agenesis of the corpus callosum, seizures, congenital heart defects, microcephaly, short stature, hypotonia, and Hirschsprung disease. The current study investigated sleep disturbance in people with MWS.

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Jun
2015

Zimmermann-Laband syndrome (ZLS) is a developmental disorder characterized by facial dysmorphism with gingival enlargement, intellectual disability, hypoplasia or aplasia of nails and terminal phalanges, and hypertrichosis. We report that heterozygous missense mutations in KCNH1 account for a considerable proportion of ZLS. KCNH1 encodes the voltage-gated K(+) channel Eag1 (Kv10.

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Jun
2014

Agenesis of the corpus callosum: a clinical approach to diagnosis.

Am J Med Genet C Semin Med Genet 2014 Jun 27;166C(2):184-97. Epub 2014 May 27.
Elizabeth Emma Palmer, David Mowat
This review article aims to guide the clinician in establishing a diagnosis in patients with agenesis of the corpus callosum (ACC), presenting antenatally or postnatally. ACC may be isolated, or occur in association with other neuroanatomical lesions and/or congenital anomalies, and has many different genetic causes. Neuropsychological outcome varies considerably from normal to profound intellectual disability depending on the etiology.

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May
2014

Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.

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Mar
2014

Health policy makers have stated that diabetes prevention is a priority; however, the type, intensity, and target of interventions or policy changes that will achieve the greatest impact remains uncertain. In response to this uncertainty, the Diabetes Population Risk Tool (DPoRT) was developed and validated to estimate future diabetes risk based on routinely collected population data. To facilitate use of DPoRT, we partnered with regional and provincial health-related decision makers in Ontario and Manitoba, Canada.

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May
2014

To evaluate the efficacy and side effects of oral mammalian target of rapamycin (mTOR) inhibitors in children and adolescents with tuberous sclerosis complex (TSC) and intractable epilepsy or subependymal giant cell astrocytoma (SEGA).
Single-center series of 13 children and adolescents with TSC who received sirolimus or everolimus (mTOR inhibitors). The anticonvulsant response was evaluated in 7 patients with TSC and refractory seizures.

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Feb
2014

Leigh syndrome (LS) is a severe neurodegenerative disorder with characteristic bilateral lesions, typically in the brainstem and basal ganglia. It usually presents in infancy and is genetically heterogeneous, but most individuals with mitochondrial complex IV (or cytochrome c oxidase) deficiency have mutations in the biogenesis factor SURF1. We studied eight complex IV-deficient LS individuals from six families of Lebanese origin.

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Sep
2014

This project involved development of a Health Background Study (HBS) Framework to support consideration of health impacts within municipalities' approval process for land use development.
Peel Public Health and Toronto Public Health led the project with the participation of planners, urban designers, engineers, public health staff and development industry representatives.
Historical growth in the Region of Peel and suburban Toronto has resulted in extensive low-density development, creating car-dependent communities with disconnected streets and segregated land uses.

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Sep
2014

Healthy Canada by Design: Translating science into action and prevention.

Can J Public Health 2014 Sep 12;106(1 Suppl 1):eS3-4. Epub 2014 Sep 12.
David L Mowat

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Feb
2014

Chromosomal microarray (CMA) is the first-line diagnostic test for individuals with intellectual disability, autism, or multiple congenital anomalies, with a 10-20% diagnostic yield. An ongoing challenge for the clinician and laboratory scientist is the interpretation of variants of uncertain significance (VOUS)-usually rare, unreported genetic variants. Laboratories differ in their threshold for reporting VOUS, and clinical practice varies in how this information is conveyed to the family and what follow-up is arranged.

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Jul
2012

The purpose of this paper is to examine whether the elevated rate of low birth weight (LBW) in the Region of Peel, Ontario can be attributed to the high proportion of immigrants in the population. In addition, we examined how the infant birth weight distribution in Peel differs by maternal region of birth.
Provincial live birth registration data were used to compare rates of LBW, preterm birth and small-for-gestational-age (SGA) births in Peel and Ontario for the years 2002 through 2006 by maternal region of birth.

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Jun
2013

Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain.

Hum Mutat 2013 Jun 12;34(6):801-11. Epub 2013 Apr 12.
Partha Sen, Yaping Yang, Colby Navarro, Iris Silva, Przemyslaw Szafranski, Katarzyna E Kolodziejska, Avinash V Dharmadhikari, Hasnaa Mostafa, Harry Kozakewich, Debra Kearney, John B Cahill, Merrissa Whitt, Masha Bilic, Linda Margraf, Adrian Charles, Jack Goldblatt, Kathleen Gibson, Patrick E Lantz, A Julian Garvin, John Petty, Zeina Kiblawi, Craig Zuppan, Allyn McConkie-Rosell, Marie T McDonald, Stacey L Peterson-Carmichael, Jane T Gaede, Binoy Shivanna, Deborah Schady, Philippe S Friedlich, Stephen R Hays, Irene Valenzuela Palafoll, Ulrike Siebers-Renelt, Axel Bohring, Laura S Finn, Joseph R Siebert, Csaba Galambos, Lananh Nguyen, Melissa Riley, Nicolas Chassaing, Adeline Vigouroux, Gustavo Rocha, Susana Fernandes, Jane Brumbaugh, Kari Roberts, Luk Ho-Ming, Ivan F M Lo, Stephen Lam, Romana Gerychova, Marta Jezova, Iveta Valaskova, Florence Fellmann, Katayoun Afshar, Eric Giannoni, Vincent Muhlethaler, Jinlong Liang, Jacques S Beckmann, Janet Lioy, Hitesh Deshmukh, Lakshmi Srinivasan, Daniel T Swarr, Melissa Sloman, Charles Shaw-Smith, Rosa Laura van Loon, Cecilia Hagman, Yves Sznajer, Catherine Barrea, Christine Galant, Thierry Detaille, Jennifer A Wambach, F Sessions Cole, Aaron Hamvas, Lawrence S Prince, Karin E M Diderich, Alice S Brooks, Robert M Verdijk, Hari Ravindranathan, Ella Sugo, David Mowat, Michael L Baker, Claire Langston, Stephen Welty, Pawel Stankiewicz
Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Nonpulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members.

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Jul
2013

Mowat-Wilson syndrome (MWS) is a severe intellectual disability (ID)-distinctive facial gestalt-multiple congenital anomaly syndrome, commonly associating microcephaly, epilepsy, corpus callosum agenesis, conotruncal heart defects, urogenital malformations and Hirschsprung disease (HSCR). MWS is caused by de novo heterozygous mutations in the ZEB2 gene. The majority of mutations lead to haplo-insufficiency through premature stop codons or large gene deletions.

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May
2013

Warburg Micro syndrome and Martsolf syndrome (MS) are heterogeneous autosomal-recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Causative biallelic germline mutations have been identified in RAB3GAP1, RAB3GAP2, or RAB18, each of which encode proteins involved in membrane trafficking. This report provides an up to date overview of all known disease variants identified in 29 previously published families and 52 new families.

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Dec
1969

A public health department in Ontario, Canada, set a 10-year strategic direction for evidence-informed decision making, defined as the systematic application of research evidence to program decisions. The multifaceted approach has identified eight key lessons for leadership, funding, infrastructure, staff development, partnerships, and change management. Results after 4 years include systematic and transparent application of research to > 15 program decisions and, increasingly, evidence-informed decision making as a cultural norm.

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Jun
2012

Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum.

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Feb
2012

Core competencies for public health in Canada require proficiency in evidence informed decision making (EIDM). However, decision makers often lack access to information, many workers lack knowledge and skills to conduct systematic literature reviews, and public health settings typically lack infrastructure to support EIDM activities. This research was conducted to explore and describe critical factors and dynamics in the early implementation of one public health unit's strategic initiative to develop capacity to make EIDM standard practice.

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Feb
2012

Chromosomal microarray or molecular karyotype has become the first-line genetic investigation for children with intellectual disability, autistic spectrum disorder or multiple congenital anomalies. Chromosomal microarray increases the detection rate of pathogenic chromosome imbalances including submicroscopic deletions or duplications in patients with undiagnosed intellectual disability to approximately 15% compared with 3% with conventional cytogenetics. This review article summarises the diagnostic technique and highlights the advantages and limitations of chromosomal microarray.

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Feb
2012

Mowat-Wilson syndrome (MWS) is caused by a heterozygous mutation or deletion of the ZEB2 gene. It is characterized by a distinctive facial appearance in association with intellectual disability (ID) and variable other features including agenesis of the corpus callosum, seizures, congenital heart defects, microcephaly, short stature, hypotonia, and Hirschsprung disease. The current study investigated the behavioral phenotype of MWS.

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Mar
2012

Renal coloboma syndrome, also known as papillorenal syndrome is an autosomal-dominant disorder characterized by ocular and renal malformations. Mutations in the paired-box gene, PAX2, have been identified in approximately half of individuals with classic findings of renal hypoplasia/dysplasia and abnormalities of the optic nerve. Prior to 2011, there was no actively maintained locus-specific database (LSDB) cataloguing the extent of genetic variation in the PAX2 gene and phenotypic variation in individuals with renal coloboma syndrome.

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Apr
2012

The aims of this study were to determine the incidence and types of haemoglobinopathies in Australian children and their distribution among ethnic groups, and to collect information on timing of diagnosis of haemoglobinopathies in Australia.
Between January 2004 and March 2006, the Australian Paediatric Surveillance Unit asked paediatricians to report all children under 15 years of age with a newly diagnosed haemoglobinopathy. A questionnaire requesting further information was forwarded to those clinicians.

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Oct
2011

This study aims to describe the phenotypic and genotypic characteristics of 45 Australian patients with tuberous sclerosis complex (TSC), to assess risk factors for intellectual disability, to compare patients with TSC1 and TSC2 mutations and to assess adherence to surveillance recommendations.
Phenotypic features were recorded in 45 patients who fulfilled established criteria for a diagnosis of definite TSC. All patients underwent TSC1 and TSC2 sequencing and multiplex ligand probe amplification.

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Mar
2010


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Jun
2010

Overgrowth.

Arch Dis Child 2010 Jun 6;95(6):458-63. Epub 2010 Apr 6.
Charles F Verge, David Mowat
Overgrowth presenting at birth requires blood glucose monitoring while a cause is sought. Among older children presenting with tall stature, common causes such as familial tall stature and simple obesity must be distinguished from rarer endocrine and genetic causes. Several genetic overgrowth syndromes carry increased risk of malignancy and regular screening is recommended.

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Jan
2010

A significant component of the variation in cognitive disability that is observed in Duchenne muscular dystrophy (DMD) is known to be under genetic regulation. In this study we report correlations between standardised measures of intelligence and mutational class, mutation size, mutation location and the involvement of dystrophin isoforms.
Sixty two male subjects were recruited as part of a study of the cognitive spectrum in boys with DMD conducted at the Sydney Children's Hospital (SCH).

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Jan
2010

1) To describe the community health nursing workforce in Canada; 2) To compare, across political jurisdictions and community health sectors, what helps and hinders community nurses to work effectively; 3) To identify organizational attributes that support one community subsector--public health nurses--to practise the full scope of their competencies.
Our study included an analysis of the Canadian Institute for Health Information nursing databases (1996-2007), a survey of over 13,000 community health nurses across Canada and 23 focus groups of public health policy-makers and front-line public health nurses.
Over 53,000 registered and licensed practical nurses worked in community health in Canada in 2007, about 16% of the nursing workforce.

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Sep
2009

To understand the perceptions and attitudes of Canadian medical students toward their undergraduate medical public health curriculum and to identify student suggestions and priorities for curriculum change.
Five focus groups of 11 or 12 medical students from all years of medical school were recruited at McMaster University Faculty of Health Sciences, Université de Sherbrooke Faculty of Medicine and Health Sciences, University of Toronto Faculty of Medicine, University of Manitoba Faculty of Medicine, and University of British Columbia Faculty of Medicine between February and April 2006. A professional facilitator was hired to conduct the focus groups using a unique, computer-based facilitation system.

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Sep
2009

Following the SARS outbreak, large gaps in the public health workforce have been identified. This study sought to understand the perceptions and attitudes of Canadian medical students with regard to public health to determine how this impacted their choice towards a career in Community Medicine (CM).
Five focus groups of 11-12 medical students from all years were recruited at McMaster University, Université de Sherbrooke, University of Toronto, University of Manitoba and the University of British Columbia.

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Jul
2009

Saethre-Chotzen syndrome (SCS) is a rare autosomal dominant syndrome involving craniosynostosis, craniofacial abnormalities, and syndactyly. A recent Scandinavian study reported an increased risk of breast cancer in individuals with a clinical diagnosis of SCS. Because of the potential importance of this finding, we organized a multicenter study enrolling people with TWIST1 mutation confirmed SCS to determine if an increased risk of cancer is present.

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Dec
2008

We have previously reported a group of patients with congenital onset weakness associated with a deficiency of members of the syntrophin-alpha-dystrobrevin subcomplex and have demonstrated that loss of syntrophin and dystrobrevin from the sarcolemma of skeletal muscle can also be associated with denervation. Here, we have further studied four individuals from a consanguineous Egyptian family with a lethal congenital myopathy inherited in an autosomal-recessive fashion and characterized by a secondary loss of beta2-syntrophin and alpha-dystrobrevin from the muscle sarcolemma, central nervous system involvement, and fetal akinesia. We performed homozygosity mapping and candidate gene analysis and identified a mutation that segregates with disease within CNTN1, the gene encoding for the neural immunoglobulin family adhesion molecule, contactin-1.

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Sep
2008

The collagen VI muscular dystrophies, Bethlem myopathy and Ullrich congenital muscular dystrophy, form a continuum of clinical phenotypes. Glycine mutations in the triple helix have been identified in both Bethlem and Ullrich congenital muscular dystrophy, but it is not known why they cause these different phenotypes.
We studied eight new patients who presented with a spectrum of clinical severity, screened the three collagen VI messenger RNA for mutations, and examined collagen VI biosynthesis and the assembly pathway.

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Nov
2008

Blepharophimosis syndrome (BPES) is caused by loss-of-function mutations in the single-exon forkhead transcription factor gene FOXL2 and by genomic rearrangements of the FOXL2 locus. Here, we focus on 92 new intragenic FOXL2 mutations, 34 of which are novel. Specifically, we found 10 nonsense mutations (11%), 13 missense mutations (14%), 40 deletions or insertions leading to a frameshift (43%), and 29 in-frame changes (32%), of which 28 (30%) lead to a polyalanine expansion.

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