Publications by authors named "Connor Scott"

16 Publications

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A unified route for flavivirus structures uncovers essential pocket factors conserved across pathogenic viruses.

Nat Commun 2021 06 1;12(1):3266. Epub 2021 Jun 1.

Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia.

The epidemic emergence of relatively rare and geographically isolated flaviviruses adds to the ongoing disease burden of viruses such as dengue. Structural analysis is key to understand and combat these pathogens. Here, we present a chimeric platform based on an insect-specific flavivirus for the safe and rapid structural analysis of pathogenic viruses. We use this approach to resolve the architecture of two neurotropic viruses and a structure of dengue virus at 2.5  Å, the highest resolution for an enveloped virion. These reconstructions allow improved modelling of the stem region of the envelope protein, revealing two lipid-like ligands within highly conserved pockets. We show that these sites are essential for viral growth and important for viral maturation. These findings define a hallmark of flavivirus virions and a potential target for broad-spectrum antivirals and vaccine design. We anticipate the chimeric platform to be widely applicable for investigating flavivirus biology.
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http://dx.doi.org/10.1038/s41467-021-22773-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169900PMC
June 2021

A chimeric dengue virus vaccine candidate delivered by high density microarray patches protects against infection in mice.

NPJ Vaccines 2021 May 7;6(1):66. Epub 2021 May 7.

Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia.

Dengue viruses (DENV) cause an estimated 390 million infections globally. With no dengue-specific therapeutic treatment currently available, vaccination is the most promising strategy for its control. A wide range of DENV vaccines are in development, with one having already been licensed, albeit with limited distribution. We investigated the immunogenicity and protective efficacy of a chimeric virus vaccine candidate based on the insect-specific flavivirus, Binjari virus (BinJV), displaying the structural prM/E proteins of DENV (BinJ/DENV2-prME). In this study, we immunized AG129 mice with BinJ/DENV2-prME via a needle-free, high-density microarray patch (HD-MAP) delivery system. Immunization with a single, 1 µg dose of BinJ/DENV2-prME delivered via the HD-MAPs resulted in enhanced kinetics of neutralizing antibody induction when compared to needle delivery and complete protection against mortality upon virus challenge in the AG129 DENV mouse model.
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http://dx.doi.org/10.1038/s41541-021-00328-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105366PMC
May 2021

Preclinical development of a molecular clamp-stabilised subunit vaccine for severe acute respiratory syndrome coronavirus 2.

Clin Transl Immunology 2021 5;10(4):e1269. Epub 2021 Apr 5.

CSIRO Manufacturing Parkville VIC Australia.

Objectives: Efforts to develop and deploy effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue at pace. Here, we describe rational antigen design through to manufacturability and vaccine efficacy of a prefusion-stabilised spike (S) protein, Sclamp, in combination with the licensed adjuvant MF59 'MF59C.1' (Seqirus, Parkville, Australia).

Methods: A panel recombinant Sclamp proteins were produced in Chinese hamster ovary and screened to select a lead vaccine candidate. The structure of this antigen was determined by cryo-electron microscopy and assessed in mouse immunogenicity studies, hamster challenge studies and safety and toxicology studies in rat.

Results: In mice, the Sclamp vaccine elicits high levels of neutralising antibodies, as well as broadly reactive and polyfunctional S-specific CD4 and cytotoxic CD8 T cells . In the Syrian hamster challenge model ( = 70), vaccination results in reduced viral load within the lung, protection from pulmonary disease and decreased viral shedding in daily throat swabs which correlated strongly with the neutralising antibody level.

Conclusion: The SARS-CoV-2 Sclamp vaccine candidate is compatible with large-scale commercial manufacture, stable at 2-8°C. When formulated with MF59 adjuvant, it elicits neutralising antibodies and T-cell responses and provides protection in animal challenge models.
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http://dx.doi.org/10.1002/cti2.1269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021130PMC
April 2021

Tau-proximity ligation assay reveals extensive previously undetected pathology prior to neurofibrillary tangles in preclinical Alzheimer's disease.

Acta Neuropathol Commun 2021 01 28;9(1):18. Epub 2021 Jan 28.

Department of Brain Sciences, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK.

Background: Multimerization is a key process in prion-like disorders such as Alzheimer's disease (AD), since it is a requirement for self-templating tau and beta-amyloid amyloidogenesis. AT8-immunohistochemistry for hyperphosphorylated tau is currently used for the diagnosis and staging of tau pathology. Given that tau-tau interactions can occur in the absence of hyperphosphorylation or other post-translational modifications (PTMs), the direct visualization of tau multimerization could uncover early pathological tau multimers.

Methods: Here, we used bimolecular fluorescent complementation, rapamycin-dependent FKBP/FRB-tau interaction and transmission electron microscopy to prove the in vitro specificity of tau-proximity ligation assay (tau-PLA). We then analyzed MAPT KO and P301S transgenic mice, and human hippocampus and temporal isocortex of all Braak stages with tau-PLA and compared it with immunohistochemistry for the diagnostic antibody AT8, the early phosphorylation-dependent AT180, and the conformational-dependent antibody MC1. Finally, we performed proteinase-K treatment to infer the content of amyloidogenic beta-sheet fold.

Results: Our novel tau-proximity ligation assay (tau-PLA) directly visualized tau-tau interactions in situ, and exclusively recognized tau multimers but not monomers. It elicited no signal in MAPT KO mouse brains, but extensively labelled P301S transgenic mice and AD brain. Two groups of structures were detected, a previously unreported widespread small-sized diffuse pathology and large, neurofibrillary-like lesions. Tau-PLA-labelled diffuse pathology appeared from the earliest Braak stages, mostly unaccompanied by tangle-like tau-immunohistochemistry, being significantly more sensitive than any small-sized dot-/thread-like pathology labelled by AT180-, AT8- and MC1-immunohistochemistry in most regions quantified at stages 0-II. Tau-PLA-labelled diffuse pathology was extremely sensitive to Proteinase-K, in contrast to large lesions.

Conclusions: Tau-PLA is the first method to directly visualize tau multimers both in vitro and in situ with high specificity. We find that tau multimerization appears extensively from the earliest presymptomatic Braak stages as a previously unreported type of diffuse pathology. Importantly, in our study multimerization is the earliest detectable molecular event of AD tau pathology. Our findings open a new window to the study of early tau pathology, with potential implications in early diagnosis and the design of therapeutic strategies.
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http://dx.doi.org/10.1186/s40478-020-01117-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844979PMC
January 2021

A broadly protective antibody that targets the flavivirus NS1 protein.

Science 2021 01;371(6525):190-194

Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.

There are no approved flaviviral therapies and the development of vaccines against flaviruses has the potential of being undermined by antibody-dependent enhancement (ADE). The flavivirus nonstructural protein 1 (NS1) is a promising vaccine antigen with low ADE risk but has yet to be explored as a broad-spectrum therapeutic antibody target. Here, we provide the structural basis of NS1 antibody cross-reactivity through cocrystallization of the antibody 1G5.3 with NS1 proteins from dengue and Zika viruses. The 1G5.3 antibody blocks multi-flavivirus NS1-mediated cell permeability in disease-relevant cell lines, and therapeutic application of 1G5.3 reduces viremia and improves survival in dengue, Zika, and West Nile virus murine models. Finally, we demonstrate that 1G5.3 protection is independent of effector function, identifying the 1G5.3 epitope as a key site for broad-spectrum antiviral development.
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http://dx.doi.org/10.1126/science.abb9425DOI Listing
January 2021

Detection and quantification of novel C-terminal TDP-43 fragments in ALS-TDP.

Brain Pathol 2021 Jul 29;31(4):e12923. Epub 2021 Jan 29.

Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.

The pathological hallmark of amyotrophic lateral sclerosis (ALS) is the presence of cytoplasmic inclusions, containing C-terminal fragments of the protein TDP-43. Here, we tested the hypothesis that highly sensitive mass spectrometry with parallel reaction monitoring (MS-PRM) can generate a high-resolution map of pathological TDP-43 peptide ratios to form the basis for quantitation of abnormal C-terminal TDP-43 fragment enrichment. Human cortex and spinal cord, microscopically staged for the presence of p-TDP-43, p-tau, alpha-synuclein, and beta-amyloid pathology, were biochemically fractionated and analyzed by immunoblot and MS for the detection of full-length and truncated (disease-specific) TDP-43 peptides. This informed the synthesis of heavy isotope-labeled peptides for absolute quantification of TDP-43 by MS-PRM across 16 ALS, 8 Parkinson's, 8 Alzheimer's disease, and 8 aged control cases. We confirmed by immunoblot the previously described enrichment of pathological C-terminal fragments in ALS-TDP urea fractions. Subsequent MS analysis resolved specific TDP-43 N- and C-terminal peptides, including a novel N-terminal truncation site-specific peptide. Absolute quantification of peptides by MS-PRM showed an increased C:N-terminal TDP-43 peptide ratio in ALS-TDP brain compared to normal and disease controls. A C:N-terminal ratio >1.5 discriminated ALS from controls with a sensitivity of 100% (CI 79.6-100) and specificity of 100% (CI 68-100), and from Parkinson's and Alzheimer's disease with a sensitivity of 93% (CI 70-100) and specificity of 100% (CI 68-100). N-terminal truncation site-specific peptides were increased in ALS in line with C-terminal fragment enrichment, but were also found in a proportion of Alzheimer cases with normal C:N-terminal ratio but coexistent limbic TDP-43 neuropathological changes. In conclusion this is a novel, sensitive, and specific method to quantify the enrichment of pathological TDP-43 fragments in human brain, which could form the basis for an antibody-free assay. Our methodology has the potential to help clarify if specific pathological TDP-43 peptide signatures are associated with primary or secondary TDP-43 proteinopathies.
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http://dx.doi.org/10.1111/bpa.12923DOI Listing
July 2021

Use of multi-flip angle measurements to account for transmit inhomogeneity and non-Gaussian diffusion in DW-SSFP.

Neuroimage 2020 10 1;220:117113. Epub 2020 Jul 1.

Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

Diffusion-weighted steady-state free precession (DW-SSFP) is an SNR-efficient diffusion imaging method. The improved SNR and resolution available at ultra-high field has motivated its use at 7T. However, these data tend to have severe B inhomogeneity, leading not only to spatially varying SNR, but also to spatially varying diffusivity estimates, confounding comparisons both between and within datasets. This study proposes the acquisition of DW-SSFP data at two-flip angles in combination with explicit modelling of non-Gaussian diffusion to address B inhomogeneity at 7T. Data were acquired from five fixed whole human post-mortem brains with a pair of flip angles that jointly optimize the diffusion contrast-to-noise (CNR) across the brain. We compared one- and two-flip angle DW-SSFP data using a tensor model that incorporates the full DW-SSFP Buxton signal, in addition to tractography performed over the cingulum bundle and pre-frontal cortex using a ball & sticks model. The two-flip angle DW-SSFP data produced angular uncertainty and tractography estimates close to the CNR optimal regions in the single-flip angle datasets. The two-flip angle tensor estimates were subsequently fitted using a modified DW-SSFP signal model that incorporates a gamma distribution of diffusivities. This allowed us to generate tensor maps at a single effective b-value yielding more consistent SNR across tissue, in addition to eliminating the B dependence on diffusion coefficients and orientation maps. Our proposed approach will allow the use of DW-SSFP at 7T to derive diffusivity estimates that have greater interpretability, both within a single dataset and between experiments.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573656PMC
October 2020

Quantitative patterns of motor cortex proteinopathy across ALS genotypes.

Acta Neuropathol Commun 2020 07 2;8(1):98. Epub 2020 Jul 2.

Nuffield Department of Clinical Neurosciences, University of Oxford, Level 1, West Wing, John Radcliffe Hospital, Oxford, OX3 9DU, UK.

Degeneration of the primary motor cortex is a defining feature of amyotrophic lateral sclerosis (ALS), which is associated with the accumulation of microscopic protein aggregates in neurons and glia. However, little is known about the quantitative burden and pattern of motor cortex proteinopathies across ALS genotypes. We combined quantitative digital image analysis with multi-level generalized linear modelling in an independent cohort of 82 ALS cases to explore the relationship between genotype, total proteinopathy load and cellular vulnerability to aggregate formation. Primary motor cortex phosphorylated (p)TDP-43 burden and microglial activation were more severe in sporadic ALS-TDP disease than C9-ALS. Oligodendroglial pTDP-43 pathology was a defining feature of ALS-TDP in sporadic ALS, C9-ALS and ALS with OPTN, HNRNPA1 or TARDBP mutations. ALS-FUS and ALS-SOD1 showed less cortical proteinopathy in relation to spinal cord pathology than ALS-TDP, where pathology was more evenly spread across the motor cortex-spinal cord axis. Neuronal pTDP-43 aggregates were rare in GAD67+ and Parvalbumin+ inhibitory interneurons, consistent with predominant accumulation in excitatory neurons. Finally, we show that cortical microglia, but not astrocytes, contain pTDP-43. Our findings suggest divergent quantitative, genotype-specific vulnerability of the ALS primary motor cortex to proteinopathies, which may have implications for our understanding of disease pathogenesis and the development of genotype-specific therapies.
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http://dx.doi.org/10.1186/s40478-020-00961-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331195PMC
July 2020

Rapid intraoperative molecular genetic classification of gliomas using Raman spectroscopy.

Neurooncol Adv 2019 May-Dec;1(1):vdz008. Epub 2019 May 28.

Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, UK.

Background: The molecular genetic classification of gliomas, particularly the identification of isocitrate dehydrogenase (IDH) mutations, is critical for clinical and surgical decision-making. Raman spectroscopy probes the unique molecular vibrations of a sample to accurately characterize its molecular composition. No sample processing is required allowing for rapid analysis of tissue. The aim of this study was to evaluate the ability of Raman spectroscopy to rapidly identify the common molecular genetic subtypes of diffuse glioma in the neurosurgical setting using fresh biopsy tissue. In addition, classification models were built using cryosections, formalin-fixed paraffin-embedded (FFPE) sections and LN-18 (IDH-mutated and wild-type parental cell) glioma cell lines.

Methods: Fresh tissue, straight from neurosurgical theatres, underwent Raman analysis and classification into astrocytoma, IDH-wild-type; astrocytoma, IDH-mutant; or oligodendroglioma. The genetic subtype was confirmed on a parallel section using immunohistochemistry and targeted genetic sequencing.

Results: Fresh tissue samples from 62 patients were collected (36 astrocytoma, IDH-wild-type; 21 astrocytoma, IDH-mutated; 5 oligodendroglioma). A principal component analysis fed linear discriminant analysis classification model demonstrated 79%-94% sensitivity and 90%-100% specificity for predicting the 3 glioma genetic subtypes. For the prediction of IDH mutation alone, the model gave 91% sensitivity and 95% specificity. Seventy-nine cryosections, 120 FFPE samples, and LN18 cells were also successfully classified. Meantime for Raman data collection was 9.5 min in the fresh tissue samples, with the process from intraoperative biopsy to genetic classification taking under 15 min.

Conclusion: These data demonstrate that Raman spectroscopy can be used for the rapid, intraoperative, classification of gliomas into common genetic subtypes.
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http://dx.doi.org/10.1093/noajnl/vdz008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777649PMC
May 2019

Development of a Sensitive, Scalable Method for Spatial, Cell-Type-Resolved Proteomics of the Human Brain.

J Proteome Res 2019 04 25;18(4):1787-1795. Epub 2019 Feb 25.

Target Discovery Institute, Nuffield Department of Medicine , University of Oxford , Roosevelt Drive , Oxford , OX3 7FZ , U.K.

While nearly comprehensive proteome coverage can be achieved from bulk tissue or cultured cells, the data usually lacks spatial resolution. As a result, tissue based proteomics averages protein abundance across multiple cell types and/or localizations. With proteomics platforms lacking sensitivity and throughput to undertake deep single-cell proteome studies in order to resolve spatial or cell type dependent protein expression gradients within tissue, proteome analysis has been combined with sorting techniques to enrich for certain cell populations. However, the spatial resolution and context is lost after cell sorting. Here, we report an optimized method for the proteomic analysis of neurons isolated from post-mortem human brain by laser capture microdissection (LCM). We tested combinations of sample collection methods, lysis buffers and digestion methods to maximize the number of identifications and quantitative performance, identifying 1500 proteins from 60 000 μm of 10 μm thick cerebellar molecular layer with excellent reproducibility. To demonstrate the ability of our workflow to resolve cell type specific proteomes within human brain tissue, we isolated sets of individual Betz and Purkinje cells. Both neuronal cell types are involved in motor coordination and were found to express highly specific proteomes to a depth of 2800 to 3600 proteins.
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http://dx.doi.org/10.1021/acs.jproteome.8b00981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456870PMC
April 2019

Single-copy expression of an amyotrophic lateral sclerosis-linked TDP-43 mutation (M337V) in BAC transgenic mice leads to altered stress granule dynamics and progressive motor dysfunction.

Neurobiol Dis 2019 01 2;121:148-162. Epub 2018 Oct 2.

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. Electronic address:

Mutations in the gene encoding the RNA-binding protein TDP-43 cause amyotrophic lateral sclerosis (ALS), clinically and pathologically indistinguishable from the majority of 'sporadic' cases of ALS, establishing altered TDP-43 function and distribution as a primary mechanism of neurodegeneration. Transgenic mouse models in which TDP-43 is overexpressed only partially recapitulate the key cellular pathology of human ALS, but may also lead to non-specific toxicity. To avoid the potentially confounding effects of overexpression, and to maintain regulated spatio-temporal and cell-specific expression, we generated mice in which an 80 kb genomic fragment containing the intact human TDP-43 locus (either TDP-43 or TDP-43) and its regulatory regions was integrated into the Rosa26 (Gt(ROSA26)Sor) locus in a single copy. At 3 months of age, TDP-43 mice are phenotypically normal but by around 6 months develop progressive motor function deficits associated with loss of neuromuscular junction integrity, leading to a reduced lifespan. RNA sequencing shows that widespread mis-splicing is absent prior to the development of a motor phenotype, though differential expression analysis reveals a distinct transcriptional profile in pre-symptomatic TDP-43 spinal cords. Despite the presence of clear motor abnormalities, there was no evidence of TDP-43 cytoplasmic aggregation in vivo at any timepoint. In primary embryonic spinal motor neurons and in embryonic stem cell (ESC)-derived motor neurons, mutant TDP-43 undergoes cytoplasmic mislocalisation, and is associated with altered stress granule assembly and dynamics. Overall, this mouse model provides evidence that ALS may arise through acquired TDP-43 toxicity associated with defective stress granule function. The normal phenotype until 6 months of age can facilitate the study of early pathways underlying ALS.
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http://dx.doi.org/10.1016/j.nbd.2018.09.024DOI Listing
January 2019

Low-grade mucoepidermoid carcinoma of the intraoral minor salivary glands with cervical metastasis: report of 2 cases and review of the literature.

J Oral Maxillofac Surg 2010 Jun 3;68(6):1396-9. Epub 2010 Apr 3.

Department of Oral and Maxillofacial Surgery, University of Illinois at Chicago, Chicago, IL 60612-7210, USA.

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http://dx.doi.org/10.1016/j.joms.2009.12.019DOI Listing
June 2010

Predictors of postoperative urinary retention.

Am Surg 2009 Oct;75(10):922-4

Santa Barbara Cottage Hospital, Pueblo at Bath, Santa Barbara, CA 93105, USA.

Postoperative urinary retention (PUR) rates vary greatly depending on the population studied. PUR leads to urinary tract instrumentation, which causes increased hospital costs and morbidity. We sought to determine our PUR rate and the risk factors that associated with it. One hundred seventy-six adult surgical inpatients were included in the study. Excluded were those receiving intraoperative catheterization, epidural anesthesia, and urologic procedures. The study population included 42 per cent spinal, 24 per cent laparoscopic abdominal, 20 per cent neck surgeries excluding the spine, and 14 per cent miscellaneous surgeries. Patient bladder volumes were determined using ultrasound scanning at three different intervals: a postvoid residual just before transfer to the operating suite, immediately on arrival in the recovery unit, and then immediately before transfer to the ward. Our overall rate of PUR was 5.7 per cent (10 of 176), defined as the need for catheterization during the postoperative hospitalization. Associated with PUR were advanced age (P = 0.0292) and postoperative bladder volume (P = 0.0246). Preoperative bladder volume, intraoperative fluid, and operative time did not reach statistical significance as being predictive of urinary retention. Our data suggest that PUR is associated with increased bladder volumes on arrival to the recovery room. A prospective study to determine whether identification of patients at risk will lead to decreased incidence of urinary tract infection is warranted.
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http://dx.doi.org/10.1177/000313480907501012DOI Listing
October 2009

Surgical management of the odontogenic keratocyst.

Oral Maxillofac Surg Clin North Am 2003 Aug;15(3):383-92

Division of Oral and Maxillofacial Surgery, Louisiana State University School of Medicine, 1501 Kings Highway, Shreveport, LA 71103, USA.

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http://dx.doi.org/10.1016/S1042-3699(03)00042-6DOI Listing
August 2003

Positron emission tomography (PET) positive thyroid incidentaloma: the risk of malignancy observed in a tertiary referral center.

Am Surg 2006 Mar;72(3):272-5

Department of Surgery, Division of Surgical Oncology, Biomedical Research Foundation of Northwest Louisiana, Shreveport, Louisiana, USA.

An incidental finding of focal thyroid uptake (thyroid incidentaloma) from an 18F-fluorodeoxyglucose positron emission tomography (PET) positron presents a diagnostic challenge. We evaluated the incidence of thyroid incidentaloma identified by PET scans and the likelihood of malignancy associated with this finding. Records from all patients from January 1, 2000 to November 30, 2003 who had focal thyroid uptake without any history of thyroid disease were culled. Of the 6241 PET scans performed, focal thyroid uptake was observed in 76 patients (1.2%). Only 14 patients (18%) underwent biopsy. Four of 14 patients (28.6%) had papillary thyroid carcinoma, 7 (50%) had hyperplasia, and 1 each had thyroiditis, nodular goiter, and follicular neoplasm. The incidence of PET thyroid incidentalomas was 1.2 per cent and the incidence of malignancy was 28.6 per cent. Given the high likelihood of malignancy, a further diagnostic workup for surgically fit patients is warranted.
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March 2006

Management of the aging forehead: a review.

Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003 Jun;95(6):642-8

Louisiana State University, Shreveport, LA 71130-3932, USA.

Aging in the upper third of the face manifests as rhytids and ptosis of the frontal, glabellar, and brow regions. Frown lines may occur even in younger individuals as a result of habitual or dynamic forehead muscular hyperactivity. Multiple treatment options have been advocated to address forehead rhytids and brow ptosis. This article reviews 3 of the more commonly used treatment options: collagen, botulinum toxin, and surgical forehead lifting. Additionally, an algorithm is proposed as a guideline for selecting the most appropriate option for a given condition.
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http://dx.doi.org/10.1067/moe.2003.240DOI Listing
June 2003