Publications by authors named "Stephanie Lam"

55 Publications

Inhibition of Na+/H+ exchanger modulates microglial activation and scar formation following microelectrode implantation.

J Neural Eng 2021 Feb 23. Epub 2021 Feb 23.

Department of Bioengineering, University of Pittsburgh, 208 Center for Biotechnology, 300 Technology Dr, Pittsburgh, PA 15219, USA, Pittsburgh, Pennsylvania, 15219, UNITED STATES.

Objective: Intracortical microelectrodes are an important tool for neuroscience research and have great potential for clinical use. However, the use of microelectrode arrays to treat neurological disorders and control prosthetics is limited by biological challenges such as glial scarring, which can impair chronic recording performance. Microglia activation is an early and prominent contributor to glial scarring. After insertion of a cortical microelectrode, nearby microglia transition into a state of activation, migrate, and encapsulate the device. Na+/H+ exchanger isoform-1 (NHE-1) is involved in various microglial functions, including their polarity and motility, and has been implicated in pro-inflammatory responses to tissue injury. HOE-642 (cariporide) is an inhibitor of NHE-1 and has been shown to depress microglial activation and inflammatory response in brain injury models.

Approach: In this study, the effects of HOE-642 treatment on microglial interactions to intracortical microelectrodes was evaluated using two-photon microscopy in vivo.

Main Results: The rate at which microglia processes and soma migrate in response to electrode implantation was unaffected by HOE-642 administration. However, HOE-642 administration effectively reduced the radius of microglia activation at 72 hours post-implantation from 222.2 µm to 177.9 µm. Furthermore, treatment with HOE-642 significantly reduced microglial encapsulation of implanted devices at 5 hours post-insertion from 50.7 ± 6.0% to 8.9 ± 6.1%, which suggests an NHE-1-specific mechanism mediating microglia reactivity and gliosis during implantation injury.

Significance: This study implicates NHE-1 as a potential target of interest in microglial reactivity and HOE-642 as a potential treatment to attenuate the glial response and scar formation around implanted intracortical microelectrodes.
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http://dx.doi.org/10.1088/1741-2552/abe8f1DOI Listing
February 2021

The Underlying Biology and Therapeutic Vulnerabilities of Leptomeningeal Metastases in Adult Solid Cancers.

Cancers (Basel) 2021 Feb 10;13(4). Epub 2021 Feb 10.

Goodman Cancer Research Centre, Faculty of Medicine, McGill University, Montreal, QC H3A 1A3, Canada.

Metastasis to the central nervous system occurs in approximately 20% of patients with advanced solid cancers such as lung cancer, breast cancer, and melanoma. While central nervous system metastases most commonly form in the brain parenchyma, metastatic cancer cells may also reside in the subarachnoid space surrounding the brain and spinal cord to form tumors called leptomeningeal metastases. Leptomeningeal metastasis involves cancer cells that reach the subarachnoid space and proliferate in the cerebrospinal fluid compartment within the leptomeninges, a sequela associated with a myriad of symptoms and poor prognosis. Cancer cells exposed to cerebrospinal fluid in the leptomeninges must contend with a unique microenvironment from those that establish within the brain or other organs. Leptomeningeal lesions provide a formidable clinical challenge due to their often-diffuse infiltration within the subarachnoid space. The molecular mechanisms that promote the establishment of leptomeningeal metastases have begun to be elucidated, demonstrating that it is a biological entity distinct from parenchymal brain metastases and is associated with specific molecular drivers. In this review, we outline the current state of knowledge pertaining to the diagnosis, treatment, and molecular underpinnings of leptomeningeal metastasis.
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http://dx.doi.org/10.3390/cancers13040732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916586PMC
February 2021

Trends in Peripheral Nerve Block Usage in Mastectomy and Lumpectomy: Analysis of a National Database From 2010 to 2018.

Anesth Analg 2021 Jan 21. Epub 2021 Jan 21.

From the Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: Compared to general anesthesia, regional anesthesia confers several benefits including improved pain control and decreased postoperative opioid consumption. While the benefits of peripheral nerve blocks (PNB) have been well studied, there are little epidemiological data on PNB usage in mastectomy and lumpectomy procedures. The primary objective of our study was to assess national trends of the annual proportion of PNB use in breast surgery from 2010 to 2018. We also identified factors associated with PNB use for breast surgery.

Methods: We identified lumpectomy and mastectomy surgical cases with and without PNB between 2010 and 2018 using the Anesthesia Quality Institute National Anesthesia Clinical Outcomes Registry (AQI NACOR). We modeled the nonlinear association between year of procedure and PNB use with segmented mixed-effects logistic regression clustered on facility identifier. The association between PNB use and year of procedure, age, sex, American Society of Anesthesiologists physical status (ASA PS), facility type, facility region, weekday, and tissue expander use was also modeled using mixed-effects logistic regression.

Results: Of the 189,854 surgical cases from 2010 to 2018 that met criteria, 86.2% were lumpectomy cases and 13.8% were mastectomy cases. The proportion of lumpectomy cases with PNB was <0.1% in 2010 and increased each subsequent year to 1.9% in 2018 (trend P < .0001). The proportion of mastectomy cases with PNB was 0.5% in 2010 and 13% in 2018 (trend P < .0001). The year 2014 was the breakpoint selected for segmented regression. Before 2014, the odds of PNB among the mastectomy cases was not significantly different from year to year. After 2014, the odds of PNB increased by 2.24-fold each year (95% confidence interval [CI], 2.00-2.49; P < .001); interaction test for pre-2014 versus post-2014 was P < .001. Similar trends were seen in the lumpectomy cases, where after 2014, the odds of PNB increased by 2.03-fold (95% CI, 1.81-2.27; P < .001); interaction test for pre-2014 versus post-2014 was P < .001. In the mastectomy cohort, year of procedure ≥2014, female sex, facility region, and tissue expander use were associated with higher odds of PNB. For lumpectomy cases, year of procedure ≥2014 and facility region were associated with higher odds of PNB use.

Conclusions: We found increased annual utilization of PNB for mastectomy and lumpectomy since 2010, although absolute prevalence is low. PNB use was associated with year of procedure for both lumpectomy and mastectomy, particularly post-2014.
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http://dx.doi.org/10.1213/ANE.0000000000005368DOI Listing
January 2021

Printable Nonenzymatic Glucose Biosensors Using Carbon Nanotube-PtNP Nanocomposites Modified with AuRu for Improved Selectivity.

ACS Biomater Sci Eng 2020 Sep 12;6(9):5315-5325. Epub 2020 Aug 12.

Weldon School of Biomedical Engineering, Birck Nanotechnology Center, Center for Implantable Devices, Purdue University, West Lafayette, Indiana 47907, United States.

Nonenzymatic glucose biosensors have the potential for a more reliable in vivo functionality due to the reduced risk of biorecognition element degradation. However, these novel sensing mechanisms often are nanoparticle-based and have nonlinear responses, which makes it difficult to gauge their potential utility against more conventional enzymatic biosensors. Moreover, these nonenzymatic biosensors often suffer from poor selectivity that needs to be better addressed before being used in vivo. To address these problems, here we present an amperometric nonenzymatic glucose biosensor fabricated using one-step electrodeposition of Au and Ru nanoparticles on the surface of a carbon-nanotube-based platinum-nanoparticle hybrid in conductive polymer. Using benchtop evaluations, we demonstrate that the bimetallic catalyst of Au-Ru nanoparticles can enable the nonenzymatic detection of glucose with a superior performance and stability. Furthermore, our biosensor shows good selectivity against other interferents, with a nonlinear dynamic range of 1-19 mM glucose. The Au-Ru catalyst has a conventional linear range of 1-10 mM, with a sensitivity of 0.2347 nA/(μM mm) ± 0.0198 ( = 3) and a limit of detection of 0.068 mM (signal-to-noise, / = 3). The biosensor also exhibits a good repeatability and stability at 37 °C over a 3 week incubation period. Finally, we use a modified Butler-Volmer nonlinear analytical model to evaluate the impact of geometrical and chemical design parameters on our nonenzymatic biosensor's performance, which may be used to help optimize the performance of this class of biosensors.
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http://dx.doi.org/10.1021/acsbiomaterials.0c00647DOI Listing
September 2020

Invasive growth associated with Cold-Inducible RNA-Binding Protein expression drives recurrence of surgically resected brain metastases.

Neuro Oncol 2021 Jan 12. Epub 2021 Jan 12.

Division of Experimental Medicine, Montréal, Québec, Canada.

Background: Sixty percent of surgically resected brain metastases (BrM) recur within 1 year. These recurrences have long been thought to result from the dispersion of cancer cells during surgery. We tested the alternative hypothesis that invasion of cancer cells into the adjacent brain plays a significant role in local recurrence and shortened overall survival.

Methods: We determined the invasion pattern of 164 surgically resected BrM and correlated with local recurrence and overall survival. We performed single-cell RNA sequencing (scRNAseq) of >15,000 cells from BrM and adjacent brain tissue. Validation of targets was performed with a novel cohort of BrM patient-derived xenografts (PDX) and patient tissues.

Results: We demonstrate that invasion of metastatic cancer cells into the adjacent brain is associated with local recurrence and shortened overall survival. scRNAseq of paired tumor and adjacent brain samples confirmed the existence of invasive cancer cells in the tumor-adjacent brain. Analysis of these cells identified Cold-Inducible RNA-Binding Protein (CIRBP) overexpression in invasive cancer cells compared to cancer cells located within the metastases. Applying PDX models that recapitulate the invasion pattern observed in patients, we show that CIRBP is overexpressed in highly invasive BrM and is required for efficient invasive growth in the brain.

Conclusions: These data demonstrate peritumoral invasion as a driver of treatment failure in BrM that is functionally mediated by CIRBP. These findings improve our understanding of the biology underlying post-operative treatment failure and lay the groundwork for rational clinical trial development based upon invasion pattern in surgically resected brain metastases.
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http://dx.doi.org/10.1093/neuonc/noab002DOI Listing
January 2021

MitoCarta3.0: an updated mitochondrial proteome now with sub-organelle localization and pathway annotations.

Nucleic Acids Res 2021 01;49(D1):D1541-D1547

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

The mammalian mitochondrial proteome is under dual genomic control, with 99% of proteins encoded by the nuclear genome and 13 originating from the mitochondrial DNA (mtDNA). We previously developed MitoCarta, a catalogue of over 1000 genes encoding the mammalian mitochondrial proteome. This catalogue was compiled using a Bayesian integration of multiple sequence features and experimental datasets, notably protein mass spectrometry of mitochondria isolated from fourteen murine tissues. Here, we introduce MitoCarta3.0. Beginning with the MitoCarta2.0 inventory, we performed manual review to remove 100 genes and introduce 78 additional genes, arriving at an updated inventory of 1136 human genes. We now include manually curated annotations of sub-mitochondrial localization (matrix, inner membrane, intermembrane space, outer membrane) as well as assignment to 149 hierarchical 'MitoPathways' spanning seven broad functional categories relevant to mitochondria. MitoCarta3.0, including sub-mitochondrial localization and MitoPathway annotations, is freely available at http://www.broadinstitute.org/mitocarta and should serve as a continued community resource for mitochondrial biology and medicine.
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http://dx.doi.org/10.1093/nar/gkaa1011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778944PMC
January 2021

A New Simplified Visual Assessment Tool Describing Facial Morphotypes Observed and Desired in Asian Populations.

J Clin Aesthet Dermatol 2020 Apr 1;13(4):23-34. Epub 2020 Apr 1.

Ms. Corduff is with the Cosmetic Refinement Clinic in Geelong, Australia.

A group of established aesthetic physicians sought to develop treatment guidelines for assessing Asian face morphologies that reflect accurate and current beauty standards across Asia. Physicians completed surveys, debated, and voted on their clinical strategies and developed an alternative simplified visual tool of assessment (SVAT) that discerns between country variations in genetic and ideal morphotypes. Electronic and paper surveys were followed by consensus debates and voting. Established aesthetic physicians practicing regularly on Asian patients. A clinically applicable SVAT was developed, which considered facial index, mid-face projection, upper and lower face shape, submalar contour, nose length and dorsal height, eye shape and brow shape, proportion of lips-to-lower face and ratio of upper-to-lower lip, and chin shape. For facial shape change, physicians always assessed the horizontal thirds, facial symmetry, and lip-chin complex profile, and also analyzed overall face shapes and Ogee curves. Criteria for creating oval-shaped faces was also defined and included treating indications, such as loss of angularity and bilateral masseter muscle hypertrophy, narrow jawlines, and longer and wider foreheads. Critical differences and similarities in country-specific aesthetic preferences, treatment requests, and considerations or strategies were uncovered, including the inadequacy of assessing overall peripheral facial shapes. This consensus establishes the assessment and treatment criteria for achieving ideal shapes for Asian patients. Specific descriptors are affected by variations; therefore, we present the visual criteria for Asian facial morphotypes. We hope that physicians new to treating Asian patients can use this clinical information to improve their practice.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605391PMC
April 2020

Heart Rhythm Abnormalities Following Acute Verapamil Overdose.

Indian J Pediatr 2021 Mar 2;88(3):285-286. Epub 2020 Oct 2.

Division of Pediatric Critical Care Medicine, Department of Pediatrics, Comer Children's Hospital and the Pritzker School of Medicine of the University of Chicago, Chicago, IL, USA.

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http://dx.doi.org/10.1007/s12098-020-03517-3DOI Listing
March 2021

Access to Eye Care Before and After Vision Loss: A Qualitative Study Investigating Eye Care Among Persons Who Have Become Blind.

Qual Rep 2020 Jun;25(6):1473-1488

OHSU Casey Eye Institute, Portland, Oregon, USA.

Navigating access to eye care requires that patients recognize the need for screening and care, employ limited financial and social resources, manage complex health insurance policies, and access specialty clinical care. We investigated the experience of patients through the progression of vision loss to blindness, utilizing qualitative methods. We conducted structured telephone interviews with 28 persons with blindness throughout Oregon. Utilizing closed and open-ended questions, we explored patient experience on the events preceding avoidable blindness. Coding for emergent themes was conducted independently by two researchers using a constant comparative method. Participants described important barriers to accessing eye care: at the systems level, lack of access to providers and treatment; at the community level, available social support and services; and at the individual level, readiness to act and trust in providers. These findings suggest that important barriers to accessing preventive eye care, early diagnosis and treatment, vocational rehabilitation, and social services often occur at multiple levels. Access to eye care should be prioritized in efforts to reduce preventable visual impairment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486025PMC
June 2020

Fabrication and evaluation of activated carbon-Pt microparticle based glutamate biosensor.

J Electroanal Chem (Lausanne) 2020 Jun 17;866. Epub 2020 Apr 17.

Weldon School of Biomedical Engineering, Birck Nanotechnology Center, Center for Implantable Device, Purdue University, West Lafayette, IN, USA.

As one of the most abundant neurotransmitters in the brain and the spinal cord, glutamate plays many important roles in the nervous system. Precise information about the level of glutamate in the extracellular space of living brain tissue may provide new insights on fundamental understanding of the role of glutamate in neurological disorders as well as neurophysiological phenomena. Electrochemical sensor has emerged as a promising solution that can satisfy the requirement for highly reliable and continuous monitoring method with good spatiotemporal resolution for characterization of extracellular glutamate concentration. Recently, we published a method to create a simple printable glutamate biosensor using platinum nanoparticles. In this work, we introduce an even simpler and lower cost conductive polymer composite using commercially available activated carbon with platinum microparticles to easily fabricate highly sensitive glutamate biosensor using direct ink writing method. The fabricated biosensors are functionality superior than previously reported with the sensitivity of 5.73 ± 0.078 nA μM mm, detection limit of 0.03 μM, response time less than or equal to 1 s, and a linear range from 1 μM up to 925 μM. In this study, we utilize astrocyte cell culture to demonstrate our biosensor's ability to monitor glutamate uptake process. We also demonstrate direct measurement of glutamate release from optogenetic stimulation in mouse primary visual cortex (V1) brain slices.
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http://dx.doi.org/10.1016/j.jelechem.2020.114136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266303PMC
June 2020

An unusual case of plasmablastic lymphoma presenting as dermatomyositis.

Clin Case Rep 2020 May 10;8(5):843-847. Epub 2020 Mar 10.

Department of Haematology Royal Perth Hospital Perth WA Australia.

We report a rare case of aggressive plasmablastic lymphoma with an initial presentation of dermatomyositis. The challenges associated with the diagnosis and treatment approach are also highlighted in this case report.
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http://dx.doi.org/10.1002/ccr3.2787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250978PMC
May 2020

What directions of improvements in electrode designs should we expect in the next 5-10 years?

Bioelectron Med (Lond) 2019 Dec 28;2(3):119-122. Epub 2020 Apr 28.

Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15260, USA.

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http://dx.doi.org/10.2217/bem-2019-0023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226723PMC
December 2019

Use of gene expression profile to identify potentially relevant transcripts to myofibrillar fragmentation index trait.

Funct Integr Genomics 2020 Jul 14;20(4):609-619. Epub 2020 Apr 14.

School of Agricultural and Veterinarian Sciences, São Paulo State University (Unesp), Jaboticabal, SP, Brazil.

The myofibrillar fragmentation index (MFI) is an indicative trait for meat tenderness. Longissimus thoracis muscle samples from the 20 most extreme bulls (out of 80 bulls set) for MFI (high (n = 10) and low (n = 10) groups) trait were used to perform transcriptomic analysis, using RNA Sequencing (RNA-Seq). An average of 24.616 genes was expressed in the Nellore muscle transcriptome analysis. A total of 96 genes were differentially expressed (p value ≤ 0.001) between the two groups of divergent bulls for MFI. The HEBP2 and BDH1 genes were overexpressed in animals with high MFI. The MYBPH and MYL6, myosin encoders, were identified. The differentially expressed genes were related to increase mitochondria efficiency, especially in cells under oxidative stress conditions, and these also were related to zinc and calcium binding, membrane transport, and muscle constituent proteins, such as actin and myosin. Most of those genes were involved in metabolic pathways of oxidation-reduction, transport of lactate in the plasma membrane, and muscle contraction. This is the first study applying MFI phenotypes in transcriptomic studies to identify and understand differentially expressed genes for beef tenderness. These results suggest that differences detected in gene expression between high and low MFI animals are related to reactive mechanisms and structural components of oxidative fibers under the condition of cellular stress. Some genes may be selected as positional candidate genes to beef tenderness, MYL6, MYBPH, TRIM63, TRIM55, TRIOBP, and CHRNG genes. The use of MFI phenotypes could enhance results of meat tenderness studies.
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http://dx.doi.org/10.1007/s10142-020-00738-9DOI Listing
July 2020

Impact of mixed counter ion on saturation solubility of esylate salt of a weak basic drug to formulate physically stable and non-hemolytic ready to use injectable solution.

Int J Pharm 2019 Dec 9;572:118829. Epub 2019 Nov 9.

GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, 19426 PA, USA.

Current work investigates a typical issue in formulating a physically stable solution especially when more than one counter ions exist in the composition. The impact of different counter ions on solubilization of monohydrate esylate salt of a free base GSK-497,[BH:CHSO:HO] (1:1) (pKa value 8.0) was investigated to formulate ready to use small volume injectable solution. The concentration dependent aggregation was also appeared to be responsible for hemolytic nature of the drug, therefore a careful investigation was needed to select appropriate counter ion solution without compromising solubilization and leading into higher order aggregation. The esylate salt's native pH in water was closer to pH, thus it was risky to render the solution unbuffered. Generally, it is recommended to formulate at least two pH unit away from pH to prevent disproportionation related physical instability. This was achieved by buffering solution away from pH, using a lactate counter ion (other than esylate salt of API salt) that did not compromise solubility of the given phase and did not appear to promote higher order of aggregation. The rationale for selecting second counter ion was primarily based on the comparison of esylate salt's solubility product (K), with the K value generated from equilibrium solubility of the free base combined with several different counter ions (chloride, lactate, aspartate, citrate and tartrate) at equimolar molar ratio. This approach suggested that the use of a counter ion with higher K (lactate and aspartate) value did not compromise the solubility of original esylate salt but a higher extent of aggregation was possible if aspartate is used to achieve higher solubility. In contrary, use of a counter ion with lower K (citrate, tartrate, chloride) reduced the solubility hence did not favor higher order of aggregation. Thus, based on K comparison a rationale of selecting second counter ion to buffer the salt solution is discussed in this work and optimal formulation concentration is determined based on drug aggregation threshold in solution.
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http://dx.doi.org/10.1016/j.ijpharm.2019.118829DOI Listing
December 2019

Effect of ketamine on transcranial motor-evoked potentials during spinal surgery: a pilot study.

Br J Anaesth 2019 12 7;123(6):e530-e532. Epub 2019 Oct 7.

New York, NY, USA. Electronic address:

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http://dx.doi.org/10.1016/j.bja.2019.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993103PMC
December 2019

Validation of a Photonumeric Assessment Scale for Grading the Slope of the Asian Forehead.

Dermatol Surg 2019 08;45 Suppl 1:S38-S45

Merz Pharmaceuticals GmbH, Frankfurt, Germany.

Background: As the number of aesthetic treatments has grown, so have the number of photonumeric assessment scales used to compare the effectiveness of these aesthetic treatments in specific anatomical areas; however, these are primarily based on Caucasian features.

Objective: To assess the validity of the first aesthetic scale for assessing the slope of the Asian forehead. A secondary objective was to correlate this scale with subject demographics and baseline characteristics.

Methods: During 2 validation sessions, 13 raters assessed full frontal and lateral facial images of female (n = 28; 56.0%) and male (n = 22; 44%) subjects. For each subject, the severity of forehead sloping was graded from 0 (convex forehead, optimal forehead volume) to 4 (concave forehead, very severe sloping). Raters also assessed the age of each subject and the estimated aesthetic treatment effort required to treat each subject.

Results: Inter-rater reliability was "substantial" with scores of 0.67 and 0.68 for the first and second validation sessions, indicating high reliability. BMI showed the highest correlation with the scale and was a significant predictor in the final regression model.

Conclusion: This photonumeric assessment scale will be useful for assessing the slope of the Asian forehead in both clinical and research settings.
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http://dx.doi.org/10.1097/DSS.0000000000001997DOI Listing
August 2019

A Validated Assessment Scale for Asian Chin Projection.

Dermatol Surg 2019 08;45 Suppl 1:S30-S37

Aesthetic Breast Surgery Centre, Corduff, Australia.

Background: As the number of different aesthetic treatments increase, numerous photonumeric assessment scales have been developed and validated to measure the effectiveness of these new treatments and techniques. Photonumeric rating scales have been developed to objectively assess improvements in anatomical areas; however, these have been based on the features of Caucasian patients.

Objective: To develop and validate a Chin Projection Scale for use in the female Asian patient population.

Methods And Materials: During 2 validation sessions, 13 raters assessed full frontal and lateral facial views of 50 Asian subjects and also estimated their age and the aesthetic treatment effort required for each subject. Chin projection was rated on a scale from 0 (optimal) to 4 (very severely receding).

Results: Inter-rater reliability was 0.80 (substantial) for Validation Session 1 and 0.83 (almost perfect) for Validation Session 2. The results for Estimated Age and Estimated Treatment Effort were essentially the same.

Conclusion: This study demonstrated the validity of the first photonumeric assessment scale for assessing the appearance of the female Asian chin. This new scale will provide a standardized measure of chin projection for Asian patients in clinical practice and clinical research settings.
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http://dx.doi.org/10.1097/DSS.0000000000001996DOI Listing
August 2019

Validated Assessment Scales for the Female Asian Calf.

Dermatol Surg 2019 08;45 Suppl 1:S22-S29

Merz Pharmaceuticals GmbH, Frankfurt, Germany.

Background: Clinical photonumeric scales have been developed and validated to objectively measure the effectiveness of aesthetic treatments in specific anatomical areas; however, these are based on the typical features of Caucasian patients. No clinical scale for Asian calf appearance currently exists.

Objective: To develop and validate a calf assessment scale for use in the female Asian patient population.

Methods And Materials: During 2 validation sessions, 13 raters assessed calf images of female Asian subjects (N = 35) viewed from behind with feet flat on the floor (at rest) and on tiptoes (dynamic). Images were rated from 0 (very slim, linear profile) to 4 (very severe convex profile).

Results: Inter-rater and intra-rater reliability were "substantial" (≥0.6, intraclass correlation coefficient [ICC] and weighted kappa) for the calf-at rest, calf-dynamic, and calf summary score. Reliability was "substantial" for calf-at rest and calf-dynamic (≥0.6, ICC and weighted kappa) and "almost perfect" (0.85) for the calf summary score. BMI and calf circumference were highly correlated with scale ratings, and calf circumference was a significant predictor.

Conclusion: This new photonumeric assessment scale has value for assessing the female Asian calf, providing a standardized measure of calf appearance in clinical practice and clinical research settings.
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http://dx.doi.org/10.1097/DSS.0000000000002004DOI Listing
August 2019

Outcomes of synchronous systemic and central nervous system (CNS) involvement of diffuse large B-cell lymphoma are dictated by the CNS disease: a collaborative study of the Australasian Lymphoma Alliance.

Br J Haematol 2019 10 24;187(2):174-184. Epub 2019 Jun 24.

Austin Health, Heidelberg, Victoria, Australia.

De novo diffuse large B-cell lymphoma (DLBCL) presenting with synchronous central nervous system (CNS) and systemic disease (synDLBCL) is not well described and is excluded from clinical trials. We performed a retrospective analysis of 80 synDLBCL patients treated across 10 Australian and UK centres. Of these patients, 96% had extranodal systemic disease. CNS-directed treatment with combination intravenous cytarabine and high-dose methotrexate ("CNS-intensive") (n = 38) was associated with favourable survival outcomes compared with "CNS-conservative" strategies such as intravenous high-dose methotrexate monotherapy, intrathecal therapy and/or radiotherapy (2-year progression-free survival [PFS] 50% vs. 31%, P = 0·006; 2-year overall survival [OS] 54% vs. 44%, P = 0·037). Outcomes were primarily dictated by the ability to control the CNS disease, with 2-year cumulative CNS relapse incidence of 42% and non-CNS relapse 21%. Two-year OS for CNS-relapse patients was 13% vs. 36% for non-CNS relapses (P = 0·02). Autologous stem cell transplantation as consolidation (n = 14) was not observed to improve survival in those patients who received CNS-intensive induction when matched for induction outcomes (2-year PFS 69% vs. 56%, P = 0·99; 2-year OS 66% vs. 56%, P = 0·98). Hyperfractionated or infusional systemic treatment did not improve survival compared to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) (2-year OS 49% for both groups). Our study suggests that adequate control of the CNS disease is paramount and is best achieved by intensive CNS-directed induction.
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http://dx.doi.org/10.1111/bjh.16064DOI Listing
October 2019

Corrigendum to Facile fabrication of flexible glutamate biosensor using direct writing of platinum nanoparticle-based nanocomposite ink.

Biosens Bioelectron 2019 09 17;141:111429. Epub 2019 Jun 17.

Weldon School of Biomedical Engineering, Birck Nanotechnology Center, Center for Implantable Device, Purdue University, West Lafayette, IN, USA. Electronic address:

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http://dx.doi.org/10.1016/j.bios.2019.111429DOI Listing
September 2019

Facile fabrication of flexible glutamate biosensor using direct writing of platinum nanoparticle-based nanocomposite ink.

Biosens Bioelectron 2019 Apr 31;131:257-266. Epub 2019 Jan 31.

Weldon School of Biomedical Engineering, Birck Nanotechnology Center, Center for Implantable Device, Purdue University, West Lafayette, IN, USA. Electronic address:

Glutamate excitotoxicity is a pathology in which excessive glutamate can cause neuronal damage and degeneration. It has also been linked to secondary injury mechanisms in traumatic spinal cord injury. Conventional bioanalytical techniques used to characterize glutamate levels in vivo, such as microdialysis, have low spatiotemporal resolution, which has impeded our understanding of this dynamic event. In this study, we present an amperometric biosensor fabricated using a simple direct ink writing technique for the purpose of in vivo glutamate monitoring. The biosensor is fabricated by immobilizing glutamate oxidase on nanocomposite electrodes made of platinum nanoparticles, multi-walled carbon nanotubes, and a conductive polymer on a flexible substrate. The sensor is designed to measure extracellular dynamics of glutamate and other potential biomarkers during a traumatic spinal cord injury event. Here we demonstrate good sensitivity and selectivity of these rapidly prototyped implantable biosensors that can be inserted into a spinal cord and measure extracellular glutamate concentration. We show that our biosensors exhibit good flexibility, linear range, repeatability, and stability that are suitable for future in vivo evaluation.
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http://dx.doi.org/10.1016/j.bios.2019.01.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261495PMC
April 2019

Pediatric intradialytic hypotension: recommendations from the Pediatric Continuous Renal Replacement Therapy (PCRRT) Workgroup.

Pediatr Nephrol 2019 05 8;34(5):925-941. Epub 2019 Feb 8.

Division of Nephrology, Children's Mercy Kansas City, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.

Intradialytic hypotension (IDH) is a common adverse event resulting in premature interruption of hemodialysis, and consequently, inadequate fluid and solute removal. IDH occurs in response to the reduction in blood volume during ultrafiltration and subsequent poor compensatory mechanisms due to abnormal cardiac function or autonomic or baroreceptor failure. Pediatric patients are inherently at risk for IDH due to the added difficulty of determining and attaining an accurate dry weight. While frequent blood pressure monitoring, dialysate sodium profiling, ultrafiltration-guided blood volume monitoring, dialysate cooling, hemodiafiltration, and intradialytic mannitol and midodrine have been used to prevent IDH, they have not been extensively studied in pediatric population. Lack of large-scale studies on IDH in children makes it difficult to develop evidence-based management guidelines. Here, we aim to review IDH preventative strategies in the pediatric population and outlay recommendations from the Pediatric Continuous Renal Replacement Therapy (PCRRT) Workgroup. Without strong evidence in the literature, our recommendations from the expert panel reflect expert opinion and serve as a valuable guide.
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http://dx.doi.org/10.1007/s00467-018-4190-1DOI Listing
May 2019

Spot and Diffuse Signs: Quantitative Markers of Intracranial Hematoma Expansion at Dual-Energy CT.

Radiology 2019 01 30;290(1):179-186. Epub 2018 Oct 30.

From the Cerebrovascular Research Laboratory, Spaulding Rehabilitation Hospital, 1575 Cambridge St, Boston, MA 02138 (C.O.T.); Departments of Radiology (C.O.T., S.L., D.K., R.H.J.B., L.D.B., J.T., M.L., J.M.R., R.G.) and Emergency Medicine (J.N.G.), Massachusetts General Hospital, Boston, Mass; Departments of Physical Medicine and Rehabilitation (C.O.T.), Radiology (S.L., L.D.B., J.T., M.L., J.M.R., R.G.), and Emergency Medicine (J.N.G.), Harvard Medical School, Boston, Mass; Department of Technical Medicine, University of Twente, Enschede, the Netherlands (D.K., R.H.J.B.); Imaging Associates, Box Hill, Victoria, Australia (B.K.P.); Department of Radiology, Jewish General Hospital and McGill University, Montreal, Canada (R.F.); and Department of Radiology and Imaging Sciences, Emory University, Atlanta, Ga (R.H.).

Purpose To compare dual-energy CT with iodine quantification to single-energy CT for evaluation of the spot sign for intracranial hematoma expansion. Materials and Methods In this retrospective study, 42 patients (mean age, 66 years ± 15 [standard deviation]; 19 women) were referred for dual-energy CT assessment of intracranial hemorrhage from October 2014 to January 2017. A machine learning approach (naive Bayes classifier) was used to identify iodine markers of extravasation for risk of hematoma expansion. Specificity and sensitivity of these markers were then independently validated in 65 new patients from February 2017 to February 2018. Results Analysis of dual-energy CT images identified two features of iodine extravasation: total iodine concentration within the hematoma (I) and focal iodine concentration in the brightest spot in the hematoma (I) as predictors of expansion. The I2 score derived from these features provided a measure of expansion probability. Optimal classification threshold was an I2 score of 20 (95% confidence interval [CI]: 18, 23), leading to correct identification of 39 of 46 (85%; 95% CI: 71%, 94%) of the hematomas on the training set (sensitivity of 79% [11 of 14; 95% CI: 57%, 100%] and specificity of 88% [28 of 32; 95% CI: 76%, 99%]), and 62 of 70 (89%; 95% CI: 79%, 95%) of the hematomas on the validation set (sensitivity of 71% [10 of 14; 95% CI: 48%, 95%] and specificity of 93% [52 of 56; 95% CI: 86%, 100%]). Sensitivity, specificity, and accuracy of conventional spot sign were, respectively, 57% (eight of 14), 90% (29 of 32), and 80% (37 of 46) on the training set and 57% (eight of 14), 83% (47 of 56), and 75% (53 of 70) on the validation set. Conclusion This study identified two quantitative markers of intracranial hemorrhage expansion at dual-energy CT of the brain. The I2 score derived from these markers highlights the utility of dual-energy CT measurements of iodine content for high sensitivity risk assessment. © RSNA, 2018 Online supplemental material is available for this article.
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http://dx.doi.org/10.1148/radiol.2018180322DOI Listing
January 2019

Genetic mechanisms underlying spermatic and testicular traits within and among cattle breeds: systematic review and prioritization of GWAS results.

J Anim Sci 2018 Dec;96(12):4978-4999

Department of Animal Biosciences, Centre for Genetic Improvement of Livestock, University of Guelph, Guelph, Ontario, Canada.

Reduced bull fertility imposes economic losses in bovine herds. Specifically, testicular and spermatic traits are important indicators of reproductive efficiency. Several genome-wide association studies (GWAS) have identified genomic regions associated with these fertility traits. The aims of this study were as follows: 1) to perform a systematic review of GWAS results for spermatic and testicular traits in cattle and 2) to identify key functional candidate genes for these traits. The identification of functional candidate genes was performed using a systems biology approach, where genes shared between traits and studies were evaluated by a guilt by association gene prioritization (GUILDify and ToppGene software) in order to identify the best functional candidates. These candidate genes were integrated and analyzed in order to identify overlapping patterns among traits and breeds. Results showed that GWAS for testicular-related traits have been developed for beef breeds only, whereas the majority of GWAS for spermatic-related traits were conducted using dairy breeds. When comparing traits measured within the same study, the highest number of genes shared between different traits was observed, indicating a high impact of the population genetic structure and environmental effects. Several chromosomal regions were enriched for functional candidate genes associated with fertility traits. Moreover, multiple functional candidate genes were enriched for markers in a species-specific basis, taurine (Bos taurus) or indicine (Bos indicus). For the different candidate regions identified in the GWAS in the literature, functional candidate genes were detected as follows: B. Taurus chromosome X (BTX) (TEX11, IRAK, CDK16, ATP7A, ATRX, HDAC6, FMR1, L1CAM, MECP2, etc.), BTA17 (TRPV4 and DYNLL1), and BTA14 (MOS, FABP5, ZFPM2). These genes are responsible for regulating important metabolic pathways or biological processes associated with fertility, such as progression of spermatogenesis, control of ciliary activity, development of Sertoli cells, DNA integrity in spermatozoa, and homeostasis of testicular cells. This study represents the first systematic review on male fertility traits in cattle using a system biology approach to identify key candidate genes for these traits.
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http://dx.doi.org/10.1093/jas/sky382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276581PMC
December 2018

Correction: DNA breakpoint assay reveals a majority of gross duplications occur in tandem reducing VUS classifications in breast cancer predisposition genes.

Genet Med 2019 Jul;21(7):1669

Department of Clinical Genomics, Ambry Genetics, 15 Argonaut Drive, Aliso Viejo, California 92656, USA.

The PDF and HTML versions of the article have been updated to include the Creative Commons Attribution 4.0 International License information.
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http://dx.doi.org/10.1038/s41436-018-0276-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609259PMC
July 2019

Quantitative Analysis of and Germline Splicing Variants Using a Novel RNA-Massively Parallel Sequencing Assay.

Front Oncol 2018 27;8:286. Epub 2018 Jul 27.

Translational Genomics Laboratory, Ambry Genetics, Aliso Viejo, CA, United States.

Clinical genetic testing for hereditary breast and ovarian cancer (HBOC) is becoming widespread. However, the interpretation of variants of unknown significance (VUS) in HBOC genes, such as the clinically actionable genes and , remain a challenge. Among the variants that are frequently classified as VUS are those with unclear effects on splicing. In order to address this issue we developed a high-throughput RNA-massively parallel sequencing assay--capable to perform quantitative and qualitative analysis of transcripts in cell lines and HBOC patients. This assay is based on cloning of RT-PCR products followed by massive parallel sequencing of the cloned transcripts. To validate this assay we compared it to the RNA splicing assays recommended by members of the ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium. This comparison was performed using well-characterized lymphoblastoid cell lines (LCLs) generated from carriers of the or germline variants that have been previously described to be associated with splicing defects. CloneSeq was able to replicate the ENIGMA results, in addition to providing quantitative characterization of and germline splicing alterations in a high-throughput fashion. Furthermore, CloneSeq was used to analyze blood samples obtained from carriers of or germline sequence variants, including the novel uncharacterized alteration c.5152+5G>T, which was identified in a HBOC family. CloneSeq provided a high-resolution picture of all the transcripts induced by c.5152+5G>T, indicating it results in significant levels of exon skipping. This analysis proved to be important for the classification of c.5152+5G>T as a clinically actionable likely pathogenic variant. Reclassifications such as these are fundamental in order to offer preventive measures, targeted treatment, and pre-symptomatic screening to the correct individuals.
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http://dx.doi.org/10.3389/fonc.2018.00286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072868PMC
July 2018

DNA breakpoint assay reveals a majority of gross duplications occur in tandem reducing VUS classifications in breast cancer predisposition genes.

Genet Med 2019 03 28;21(3):683-693. Epub 2018 Jul 28.

Department of Clinical Genomics, Ambry Genetics, 15 Argonaut Drive, Aliso Viejo, California, 92656, USA.

Purpose: Gross duplications are ambiguous in terms of clinical interpretation due to the limitations of the detection methods that cannot infer their context, namely, whether they occur in tandem or are duplicated and inserted elsewhere in the genome. We investigated the proportion of gross duplications occurring in tandem in breast cancer predisposition genes with the intent of informing their classifications.

Methods: The DNA breakpoint assay (DBA) is a custom, paired-end, next-generation sequencing (NGS) method designed to capture and detect deep-intronic DNA breakpoints in gross duplications in BRCA1, BRCA2, ATM, CDH1, PALB2, and CHEK2.

Results: DBA allowed us to ascertain breakpoints for 44 unique gross duplications from 147 probands. We determined that the duplications occurred in tandem in 114 (78%) carriers from this cohort, while the remainder have unknown tandem status. Among the tandem gross duplications that were eligible for reclassification, 95% of them were upgraded to pathogenic.

Conclusion: DBA is a novel, high-throughput, NGS-based method that informs the tandem status, and thereby the classification of, gross duplications. This method revealed that most gross duplications in the investigated genes occurred in tandem and resulted in a pathogenic classification, which helps to secure the necessary treatment options for their carriers.
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http://dx.doi.org/10.1038/s41436-018-0092-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752314PMC
March 2019

Dynamic rheology as a quantitative method for real-time tracking of excipient solvation in non-aqueous hydroxypropylcellulose topical gels.

Pharm Dev Technol 2019 Apr 17;24(4):521-527. Epub 2018 Sep 17.

a GSK Dermatology Unit , Topical Product Development , Collegeville , PA , USA.

This article describes a method to quantitatively track the solvation of HPC in a non-aqueous solvent system during topical gel manufacture. Where visual observation and microscopy could not establish a trend, straight-forward rheological profiling demonstrated a correlation between increased solvation of hydroxypropyl cellulose polymer (viscosity modifier) and decreased tan δ, indicating the formation of a viscoelastic gel network over time during processing. This correlation serves as a valuable tool for process optimization and HPC solvation tracking in non-aqueous topical gel formulations.
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http://dx.doi.org/10.1080/10837450.2018.1502319DOI Listing
April 2019

PAN-ASIAN CONSENSUS-Key Recommendations for Adapting the World Congress of Dermatology Consensus on Combination Treatment with Injectable Fillers, Toxins, and Ultrasound Devices in Asian Patients.

J Clin Aesthet Dermatol 2017 Aug 1;10(8):16-27. Epub 2017 Aug 1.

Dr. Chao is with Chao and Chiu Institute of Dermatology, Taipei,Taiwan; Dr. Chhabra is with Skin Alive Clinic, New Delhi, India.

The demand for minimally invasive aesthetic procedures has driven requests by physicians for guidance on their use in Asian patients, who have unique cultural preferences, social trends, and anatomy. However, few guidelines exist, particularly on combination treatment strategies for different facial shapes or indications such as the modification of face shapes to the "oval ideal."Physicians must, therefore, apply Caucasian patient-optimized guidelines to their Asian patients. Eleven specialists developed a consensus on the use of botulinum toxin A (BoNT-A), calcium hydroxylapatite (CaHA) and hyaluronic acid (HA) fillers, and microfocused ultrasound with visualization (MFU-V) devices in Asian patients on upper-, middle-, and lower-face indications, including strategies to modify different facial shapes to the oval shape. Approval from 70 to 90 percent of all participants led to moderate consensus, while 90 percent agreement denoted a strong consensus. For early intervention/enhancement and restoration, most combination strategies are similar between Asian and Caucasian patients. Compared to Caucasian patients, however, beautification is a more common focus in Asian patients. The "ideal" oval facial shape can be created using different interventions depending on the patient's baseline characteristics. Although treatments and treatment sequences for early intervention/enhancement and restoration for beautification in Asian patients are similar to those in Caucasian patients, different treatment strategies may be required.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605210PMC
August 2017