Publications by authors named "Paul Chamberlain"

44 Publications

Axial length targets for myopia control.

Ophthalmic Physiol Opt 2021 05 5;41(3):523-531. Epub 2021 May 5.

College of Optometry, University of Houston, Houston, USA.

Purpose: Both emmetropic and myopic eyes elongate throughout childhood. The goals of this study were to compare axial elongation among untreated progressing myopes, progressing myopes treated with a myopia control contact lens and emmetropes, in order to place axial elongation in the context of normal eye growth in emmetropic children, and to consider whether normal physiological eye growth places limits on what might be achieved with myopia control.

Methods: Axial elongation data were taken from the 3-year randomised clinical trial of a myopia control dual-focus (MiSight® 1 day) contact lens. These were compared with data for myopic and emmetropic children in two large cohort studies: the Orinda Longitudinal Study of Myopia (OLSM) and the Singapore Cohort Study of the Risk Factors for Myopia (SCORM). Each study's published equations were used to calculate annual axial elongation. Four virtual cohorts-myopic and emmetropic for each model-were created, each with the same age distribution as the MiSight clinical trial subjects and the predicted cumulative elongation calculated at years 1, 2 and 3 for myopes and emmetropes using both the OLSM and SCORM models.

Results: The untreated control myopes in the MiSight clinical trial showed mean axial elongation over 3 years (0.62 mm) similar to the virtual cohorts based on the OLSM (0.70 mm) and SCORM (0.65 mm) models. The predicted 3-year axial elongation for the virtual cohorts of emmetropes was 0.24 mm for both the OLSM and SCORM models-similar to the mean 3-year elongation in MiSight-treated myopes (0.30 mm).

Conclusions: The 3-year elongation in MiSight-treated myopes approached that of virtual cohorts of emmetropes with the same age distribution. It is hypothesised that myopic axial elongation is superimposed on an underlying physiological axial elongation observed in emmetropic eyes, which reflects increases in body stature. We speculate that optically based myopia control treatments may minimise the myopic axial elongation but retain the underlying physiological elongation observed in emmetropic eyes.
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http://dx.doi.org/10.1111/opo.12812DOI Listing
May 2021

Computationally guided high-throughput design of self-assembling drug nanoparticles.

Nat Nanotechnol 2021 Jun 25;16(6):725-733. Epub 2021 Mar 25.

Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Nanoformulations of therapeutic drugs are transforming our ability to effectively deliver and treat a myriad of conditions. Often, however, they are complex to produce and exhibit low drug loading, except for nanoparticles formed via co-assembly of drugs and small molecular dyes, which display drug-loading capacities of up to 95%. There is currently no understanding of which of the millions of small-molecule combinations can result in the formation of these nanoparticles. Here we report the integration of machine learning with high-throughput experimentation to enable the rapid and large-scale identification of such nanoformulations. We identified 100 self-assembling drug nanoparticles from 2.1 million pairings, each including one of 788 candidate drugs and one of 2,686 approved excipients. We further characterized two nanoparticles, sorafenib-glycyrrhizin and terbinafine-taurocholic acid both ex vivo and in vivo. We anticipate that our platform can accelerate the development of safer and more efficacious nanoformulations with high drug-loading capacities for a wide range of therapeutics.
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http://dx.doi.org/10.1038/s41565-021-00870-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197729PMC
June 2021

Optic nerve biopsy in leukemic infiltrative optic neuropathy: a case report and review of the literature.

Orbit 2021 Feb 8:1-5. Epub 2021 Feb 8.

Department of Ophthalmology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Optic nerve infiltration is a rare but known complication of the central nervous system (CNS)-involving lymphoma and leukemic disorders. The diagnosis is often presumed and patients are empirically treated with systemic therapy and/or local radiation. Optic nerve biopsy is usually avoided due to the risk of permanent vision loss secondary to the procedure. We present a case of biopsy-proven leukemic optic neuropathy without optic nerve sheath or cerebrospinal fluid (CSF) involvement in a patient previously in remission from T-cell prolymphocytic leukemia (T-PLL). To our knowledge, this is the first documented case of T-PLL with biopsy-proven optic nerve invasion without CSF involvement and suggests possible perineural invasion or a sanctuary site from chemotherapy. We suggest that for patients with poor vision and suspected leukemic infiltration without other evidence of CNS involvement, both optic nerve and optic sheath biopsy should be performed for diagnosis and treatment.
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http://dx.doi.org/10.1080/01676830.2021.1880443DOI Listing
February 2021

Ocular health of children wearing daily disposable contact lenses over a 6-year period.

Cont Lens Anterior Eye 2021 Feb 4:101391. Epub 2021 Feb 4.

CooperVision, Inc., 6150 Stoneridge Mall Rd, Pleasanton, CA 94588, United States.

Purpose: To report on the ocular health and safety of children fit with soft hydrogel daily-disposable contact lenses, and followed for 6-years in a double-masked clinical trial investigating the performance of a dual-focus contact lens designed to control myopia progression.

Methods: Children aged 8-12 years, naïve to contact lens wear, were enrolled across four international sites. During years 1-3, children were randomised to either MiSight® 1 day or Proclear® 1 day (both omafilcon A, CooperVision, Inc.). The lenses were identical in material and geometry except for the front optical zone design. At the end of year-3, all those wearing Proclear 1 day were switched to MiSight 1 day, therefore all wore MiSight 1 day in years 4-6. Subjects agreed to wear the lenses at least 10-hours/day, 6-days/week. After dispensing, study visits were at 1-week, 1-month, 6-months and every 6-months until 6-years. At each visit, ocular measurements and subjective responses were recorded. Biomicroscopy used 0-4 grading scales; grade 0 represented no findings.

Results: 144 children were enrolled: 69F:75M; mean age 10.1 years; mean cycloplegic spherical-equivalent refraction -2.11D; ethnicities included 34 East-Asian, 12 West-Asian, and 79 Caucasian. 92 completed the 6-years. Only three subjects discontinued due to an ocular adverse event (AE). No contact lens related AEs were classified as serious. The incidence rate of infiltrative AEs was 0.61% (6.1/1000 wearing-years; 95%CI: 0.24%-1.57%). The most common biomicroscopy findings were limbal, bulbar and tarsal hyperaemia and tarsal roughness. 99% of all biomicroscopy findings were grade-1 or lower. After 6-years of lens wear, ocular health by biomicroscopy was similar to pre-lens wear.

Conclusions: Across the 6-years, there were no contact lens related serious AEs and biomicroscopy showed no significant changes. Results suggest that children this age can successfully wear daily-disposable hydrogel contact lenses with minimal impact on ocular physiology.
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http://dx.doi.org/10.1016/j.clae.2020.11.011DOI Listing
February 2021

Adverse event rates in the retrospective cohort study of safety of paediatric soft contact lens wear: the ReCSS study.

Ophthalmic Physiol Opt 2021 01 11;41(1):84-92. Epub 2020 Nov 11.

School of Optometry and Vision Science, UNSW Sydney, Sydney, NSW, Australia.

Purpose: To ascertain the safety of soft contact lens (SCL) wear in children through a retrospective chart review including real-world clinical practice settings.

Methods: The study reviewed clinical charts from 963 children: 782 patients in 7 US eye care clinics and 181 subjects from 2 international randomised clinical trials (RCTs). Subjects were first fitted while 8-12 years old with various SCL designs, prescriptions and replacement schedules, and observed through to age 16. Clinical records from visits with potential adverse events (AEs) were electronically scanned and reviewed to consensus by an Adjudication Panel.

Results: The study encompassed 2713 years-of-wear and 4611 contact lens visits. The cohort was 46% male, 60% were first fitted with daily disposable SCLs, the average age at first fitting was 10.5 years old, with a mean of 2.8 ± 1.5 years-of-wear of follow-up observed. There were 122 potential ocular AEs observed from 118/963 (12.2%) subjects; the annualised rate of non-infectious inflammatory AEs was 0.66%/year (95% CI 0.39-1.05) and 0.48%/year (0.25-0.82) for contact lens papillary conjunctivitis. After adjudication, two presumed or probable microbial keratitis (MK) cases were identified, a rate of 7.4/10 000 years-of-wear (95% CI 1.8-29.6). Both were in teenage boys and one resulted in a small scar without loss of visual acuity.

Conclusion: This study estimated the MK rate and the rate of other inflammatory AEs in a cohort of SCL wearers from 8 through to 16 years of age. Both rates are comparable to established rates among adults wearing SCLs.
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http://dx.doi.org/10.1111/opo.12753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839756PMC
January 2021

European Immunogenicity Platform 11th Open Scientific Symposium on immunogenicity of biopharmaceuticals.

Bioanalysis 2020 Aug 17;12(15):1043-1048. Epub 2020 Aug 17.

Sanofi R&D, Translational Medicine & Early Development, Frankfurt am Main 65926, Germany.

Given the expanding number of complex therapeutic protein drugs and advanced therapy medicinal products that are being developed, improving our ability to assess the potential immunogenicity of biologics is critical to ensuring treatment efficacy and patient safety. In this context, the European Immunogenicity Platform annual meeting provides opportunities for experts from industry and academia, regulators and clinicians to convene and discuss immunogenicity assessment methods and tools. This report summarizes the key messages on immunogenicity testing, prediction, clinical relevance and advanced therapy medicinal products discussed at the 11th Open Scientific European Immunogenicity Platform Symposium on Immunogenicity of Biopharmaceuticals, Lisbon, Portugal, 17-19 February 2020.
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http://dx.doi.org/10.4155/bio-2020-0150DOI Listing
August 2020

Late Implant Hemorrhage Masquerading as an Orbital Mass.

Ophthalmic Plast Reconstr Surg 2021 Mar-Apr 01;37(2):e81

Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, U.S.A.

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http://dx.doi.org/10.1097/IOP.0000000000001667DOI Listing
April 2021

Immunogenicity Risk Assessment for an Engineered Human Cytokine Analogue Expressed in Different Cell Substrates.

AAPS J 2020 04 14;22(3):65. Epub 2020 Apr 14.

Bonnie Rup Consulting, LLC, Reading, Massachusetts, USA.

The purpose of this article is to illustrate how performance of an immunogenicity risk assessment at the earliest stage of product development can be instructive for critical early decision-making such as choice of host system for expression of a recombinant therapeutic protein and determining the extent of analytical characterization and control of heterogeneity in co- and post-translational modifications. Application of a risk-based approach for a hypothetical recombinant DNA analogue of a human endogenous cytokine with immunomodulatory functions is described. The manner in which both intrinsic and extrinsic factors could interact to influence the relative scale of risk associated with expression in alternative hosts, namely Chinese hamster ovary (CHO) cells, Pichia pastoris, Escherichia coli, or Nicotinia tabacum is considered in relation to the development of the investigational product to treat an autoimmune condition. The article discusses how particular product-related variants (primary amino acid sequence modifications and post-translational glycosylation or other modifications) and process-derived impurities (host cell proteins, endotoxins, beta-glucans) associated with the different expression systems might influence the impact of immunogenicity on overall clinical benefit versus risk for a therapeutic protein candidate that has intrinsic MHC Class II binding potential. The implications of the choice of expression system for relative risk are discussed in relation to specific actions for evaluation and measures for risk mitigation, including use of in silico and in vitro methods to understand intrinsic immunogenic potential relative to incremental risk associated with non-human glycan and protein impurities. Finally, practical guidance on presentation of this information in regulatory submissions to support clinical development is provided.
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http://dx.doi.org/10.1208/s12248-020-00443-2DOI Listing
April 2020

Outcomes of Scleral Contact Lens Use in Veteran Population.

Eye Contact Lens 2020 Nov;46(6):348-352

School of Medicine (A.K., H.S., G.C., P.C.), Baylor College of Medicine, Houston, TX; Department of Ophthalmology (P.C., S.O.-N., S.K.), Cullen Eye Institute, Baylor College of Medicine, Houston, TX; and Eye Care Line (S.V., S.O.-N., S.K.), Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX.

Objectives: To document outcomes associated with use of scleral contact lenses (SL) in the veteran population and analyze the medical and demographic factors that affect these outcomes, specifically those involved in contact lens discontinuation.

Methods: A retrospective study of consecutive patients first fitted with Jupiter Scleral lenses at the Michael E. DeBakey Veterans Affairs Medical Center between 2010 and 2018. The primary outcome was continuation of SL use at 1 year. Demographic factors and variables such as presence of comorbid diseases, improvement in visual acuity, and daily lens wear time were compared. Logistic regression analysis was used to determine which factors were associated with SL discontinuation.

Results: One hundred twenty patients with a mean age of 56.7±15.1 years were fitted with SL during the study period. The most common diagnosis was corneal ectasia (55.8%). Sixty-six (55.0%) patients had difficulty with wear, the most common being ocular irritation (20.0%) and mid-day fogging or bubbles (15.8%). Forty-one patients (34.2%) discontinued SL use with a median time from fitting to discontinuation of 5.2 months. The most common reason for SL discontinuation was difficulty with insertion and removal (53.7%). Comorbid neurologic disease had a statistically significant association with discontinuation (odds ratio 4.6, 95% confidence interval 1.3-17, P=0.022). There were statistically significant differences in mean visual acuity improvement (P=0.003) and daily wear time (P<0.001) but not age (P=0.70) between patients who continued and discontinued lens use.

Conclusions: Scleral contact lenses are effective for treating a wide variety of ocular diseases and have positive outcomes in veterans. This study aids in understanding patient factors that affect outcomes of SL use in veterans. Further prospective studies are needed to make formal recommendations regarding candidate selection.
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http://dx.doi.org/10.1097/ICL.0000000000000671DOI Listing
November 2020

Pharmacodynamics, safety, and immunogenicity of Pelmeg, a pegfilgrastim biosimilar in healthy subjects.

Pharmacol Res Perspect 2019 10 13;7(5):e00507. Epub 2019 Aug 13.

Cinfa Biotech GmbH (now part of the Mundipharma network of independent associated companies) Munich Germany.

A pharmacodynamics (PD) and immunogenicity study was conducted to investigate biosimilarity of Pelmeg, a pegfilgrastim biosimilar to EU-authorized Neulasta. The multiple-dose, randomized, double-blind, two-sequence, and three-period cross-over study comprised 96 healthy male subjects, receiving Pelmeg (Test [T]) and Neulasta (Reference [R]) in a sequential manner (T-T-R vs R-R-T). Subjects were dosed with 3 mg pegfilgrastim, as this dose was previously shown to be in the ascending part of the dose-response curve for PD. The primary PD endpoint was the area under the effect curve (AUEC) for absolute neutrophil count (ANC). The primary immunogenicity endpoint was proportion of anti-drug antibody (ADA)-positive subjects at the end of Period 2 (ie, after administration of two doses of the same study drug). Comparability was demonstrated for the PD endpoint, with the geometric mean ratio (T/R) of AUEC being 101.59%, with a corresponding 95% CI of [99.58; 103.63]. Of note, when using tighter acceptance limits (90.00%-111.00%), comparability between test and reference was shown as well. Only two confirmed ADA positive samples were detected, one after treatment with Pelmeg and one after Neulasta. These had a low ADA titer, no filgrastim reactivity, and no neutralizing capacity. No clinically meaningful differences in safety between Pelmeg and Neulasta were observed. Overall, the results from this study confirmed the biosimilarity of Pelmeg and Neulasta for PD and immunogenicity, as shown already at the bioanalytical level and in the pivotal PK/PD study with Pelmeg.
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http://dx.doi.org/10.1002/prp2.507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691755PMC
October 2019

A 3-year Randomized Clinical Trial of MiSight Lenses for Myopia Control.

Optom Vis Sci 2019 08;96(8):556-567

Visioncare Research Ltd., Farnham, Surrey, United Kingdom.

Significance: Results of this randomized, double-masked clinical trial demonstrate the effectiveness of the MiSight soft contact lens in slowing myopia progression over multiple years.

Purpose: The purpose of this study was to quantify the effectiveness of MiSight daily disposable soft contact lens in slowing the progression of juvenile-onset myopia.

Methods: Myopic children (spherical equivalent refraction, -0.75 to -4.00 D; astigmatism, <1.00 D) aged 8 to 12 years with no prior contact lens experience were enrolled in a 3-year, double-masked, randomized clinical trial at four investigational sites in four countries. Subjects in each group were matched for age, sex, and ethnicity and were randomized to either a MiSight 1-day contact lens (test) or Proclear 1-day (control; omafilcon A) and worn on a daily disposable basis. Primary outcome measures were the change in cycloplegic spherical equivalent refraction and axial length.

Results: Of the subjects enrolled, 75.5% (109/144) completed the clinical trial (53 test, 56 control). Unadjusted change in spherical equivalent refraction was -0.73 D (59%) less in the test group than in the control group (-0.51 ± 0.64 vs. -1.24 ± 0.61 D, P < .001). Mean change in axial length was 0.32 mm (52%) less in the test group than in the control group (0.30 ± 0.27 vs. 0.62 ± 0.30 mm, P < .001). Changes in spherical equivalent refraction and axial length were highly correlated (r = -0.90, P < .001). Over the course of the study, there were no cases of serious ocular adverse events reported. Four asymptomatic corneal infiltrative (one test, three control) events were observed at scheduled study visits.

Conclusions: Results of this clinical trial demonstrate the effectiveness of the MiSight daily disposable soft contact lens in slowing change in spherical equivalent refraction and axial length.
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http://dx.doi.org/10.1097/OPX.0000000000001410DOI Listing
August 2019

Genotoxic Strains Encoding Colibactin, Cytolethal Distending Toxin, and Cytotoxic Necrotizing Factor in Laboratory Rats.

Comp Med 2019 04 22;69(2):103-113. Epub 2019 Mar 22.

Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts;, Email:

Although many strains are considered commensals in mammals, strains encoding the cyclomodulin genotoxins are associated with clinical and subclinical disease in the urogenital and gastrointestinal tracts, meningitis, and inflammatory disorders. These genotoxins include the polyketide synthase () pathogenicity island, cytolethal distending toxin (), and hemolysin-associated cytotoxic necrotizing factor (). strains are not excluded from rodents housed under SPF conditions in academic or vendor facilities. This study isolated and characterized genotoxin-encoding from laboratory rats obtained from 4 academic institutions and 3 vendors. A total of 69 distinct isolates were cultured from feces, rectal swab, nares, or vaginal swab of 52 rats and characterized biochemically. PCR analysis for cyclomodulin genes and phylogroup was performed on all 69 isolates. Of the 69 isolates, 45 (65%) were positive for , 20/69 (29%) were positive for , and 4 (6%) were positive for . Colibactin was the sole genotoxin identified in 21 of 45 isolates (47%), whereas or was also present in the remaining 24 isolates (53%); and were never present together or without . All genotoxin-associated strains were members of pathogen-associated phylogroup B2. Fisher exact and χ² tests demonstrated significant differences in genotoxin prevalence and API code distribution with regard to vendor. Select isolates were characterized by HeLa cell in vitro cytotoxicity assays, serotyped, and whole-genome sequenced. All isolates encoding cyclomodulins induced megalocytosis. Serotypes corresponded with vendor origin and cyclomodulin composition, with the serotype representing a known human uropathogen. Whole-genome sequencing confirmed the presence of complete , , and hemolysin- pathogenicity islands. These findings indicate that genotoxin-encoding colonize laboratory rats from multiple commercial vendors and academic institutions and suggest the potential to contribute to clinical disease and introduce confounding variables into experimental rat models.
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http://dx.doi.org/10.30802/AALAS-CM-18-000099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6464076PMC
April 2019

Effective presentation of immunogenicity risk assessments and related data in regulatory dossiers.

Authors:
Paul Chamberlain

Bioanalysis 2019 Sep 15;11(17):1581-1592. Epub 2019 Feb 15.

NDA Advisory Services, Ltd, Grove House, Guildford Road, Leatherhead, Surrey KT22 9DF, UK.

The purpose of this article is to provide practical advice about how to present immunogenicity-related information in regulatory dossiers, with a particular focus on a model for an Integrated Summary of Immunogenicity to be submitted in the marketing authorization application for novel biopharmaceutical products in ICH regions (EU, USA and Japan). A format that links the analysis of potential risk factors to a justification of the methodology applied for risk evaluation and conclusions for risk mitigation is presented as a model that can be adapted according to the weight of evidence to be submitted in support of the assessment of impact on overall clinical benefit versus risk for the particular situation.
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http://dx.doi.org/10.4155/bio-2018-0209DOI Listing
September 2019

Ophthalmic Conditions Associated with Inpatient Falls among Veterans.

Optom Vis Sci 2018 12;95(12):1114-1119

Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, Texas.

Significance: Efforts to describe the relationship between pathological visual impairment and fall risk are typically confined to community dwellers. Among admitted patients, however, the associations are less understood. Fall risk assessment tools are used in some clinical settings, but most do not capture the suspected importance of ophthalmic pathologies in predicting the likelihood of an inpatient fall.

Purpose: The purpose of this study was to determine the association between ophthalmic conditions and inpatient falls at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC), where vision and ophthalmic conditions are not considered when assessing fall risk.

Methods: This is a population-based, retrospective case-control study of 805 patients admitted to the MEDVAMC in January 2014 who had also visited the MEDVAMC Eye Clinic within 1 year of admission. The patients' eye examinations, ophthalmic diagnoses, and other indicators of constitutive health were compared between 60 patients who experienced an inpatient fall ("cases") and 749 patients who did not ("controls"). Significant differences between the cases and the controls were determined using logistic regression models.

Results: Baseline demographics were similar among the two groups. Ophthalmic conditions associated with an increased incidence of inpatient falls included age-related macular degeneration (odds ratio, 3.9; 95% confidence interval, 1.5 to 9.9; P = .008) and a presenting visual acuity of worse than 20/40 in the better-seeing eye (odds ratio, 2.0; 95% confidence interval, 1.0 to 4.1; P = .04). Those without falls demonstrated a better mean presenting visual acuity in the better-seeing eye compared with those who fell (logMAR, 0.12 ± 0.23 vs. 0.28 ± 0.49, P < .001).

Conclusions: In this population, age-related macular degeneration and poor presenting visual acuity in the better-seeing eye are associated with increased incidence of inpatient falls. An assessment of visual function and ophthalmic diagnoses may be warranted upon admission to the hospital for increased prevention of inpatient falls.
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http://dx.doi.org/10.1097/OPX.0000000000001312DOI Listing
December 2018

Preoperative Prediction of the Optimal Toric Intraocular Lens Alignment Meridian.

J Refract Surg 2018 Aug;34(8):515-520

Purpose: To determine whether any of three keratometry devices is superior to the others in predicting the ideal toric intraocular lens (IOL) alignment meridian.

Methods: A retrospective review was performed to identify patients who underwent cataract phacoemulsification with toric IOL implantation from November 2014 to November 2016 at a single academic institution. For each patient, corneal measurements were performed with an optical low-coherence reflectometer/autokeratometer (OLCR), a dual Scheimpflug/Placido analyzer, and a color light-emitting diode (LED) topographer. Postoperatively, the ideal toric IOL alignment meridian that would have resulted in the least amount of residual astigmatism was determined using the online Berdhal & Hardten Toric Results Analyzer (BHTRA). To determine the prediction error, this ideal alignment meridian was compared to the corneal meridian with the highest refractive power, as provided by the three devices.

Results: Fifty-six eyes of 56 patients were included in the study. The mean absolute errors in the toric IOL alignment meridians of the color LED topographer, dual Scheimpflug/Placido analyzer, and OLCR were 5.2° ± 5.2°, 7.6° ± 5.7°, and 5.4° ± 5.1°, respectively. There was no significant difference in the ability of each device to predict the ideal alignment meridian as determined by the BHTRA.

Conclusions: The color LED topographer, dual Scheimpflug/Placido analyzer, and OLCR may all be used to preoperatively determine the best alignment meridian for toric IOL placement. Surgeons should use their best judgment in determining which device to use in preoperative planning for individual patients. [J Refract Surg. 2018;34(8):515-520.].
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http://dx.doi.org/10.3928/1081597X-20180530-01DOI Listing
August 2018

Racial disparities in the choice of definitive treatment for squamous cell carcinoma of the oral cavity.

Head Neck 2018 11 26;40(11):2372-2382. Epub 2018 Jun 26.

Division of Otolaryngology - Head and Neck Surgery, Department of Surgery, NorthShore University HealthSystem, Evanston, Illinois.

Background: Definitive surgery is recommended for oral cavity squamous cell carcinoma (SCC). The purpose of this study was to present our assessment of the disparities in treatment selection for oral cavity SCC.

Methods: Non-Hispanic white and non-Hispanic black patients with oral cavity SCC were identified in the National Cancer Database (NCDB). Regression models were used to estimate relative risk (RR) of receiving surgery and absolute difference between non-Hispanic white and non-Hispanic black patients.

Results: There were 82.3% of non-Hispanic white patients who received surgery, compared to 64.2% of non-Hispanic black patients (P < .001). The non-Hispanic black patients were less likely to receive surgery than non-Hispanic white patients (RR 0.87) with an absolute difference of 10.9%. The non-Hispanic black patients were significantly more likely to not be offered surgery (RR 1.42) and to refuse recommended surgery (RR 1.38) but not have a contraindication to surgery (RR 1.17).

Conclusion: The non-Hispanic black patients are less likely to receive or be recommended surgery for oral cavity SCC and are more likely to refuse surgery. Further study is needed to identify strategies to close this disparity.
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http://dx.doi.org/10.1002/hed.25341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563920PMC
November 2018

Chimeric Antigen Receptor T-Cells (CAR T-Cells) for Cancer Immunotherapy - Moving Target for Industry?

Pharm Res 2018 May 31;35(8):152. Epub 2018 May 31.

NDA Group, Stockholm, Sweden.

The first CD19 CAR T-cell products, Kymriah and Yescarta, are entering the US market and also being evaluated for marketing authorization in the EU. This breakthrough has expanded the interest and also investments towards novel chimeric antigen receptor (CAR) designs, both for hematological malignancies and solid tumors. At the same time, there is active development in moving from autologous products to allogeneic, off-the-shelf -products. New manufacturing technologies are also emerging for production of these complex genetically-modified cells and even decentralized manufacturing in hospitals is under consideration. However, the high potency of CAR T-cells is associated with toxicity and not all patients respond to the treatment. In addition, the number of patient and product variables impacting the clinical outcome is high. The race towards novel CAR T treatment options for cancer patients has begun, but without careful design of the constructs and overall understanding of the factors that impact the ultimate outcome in each case, the road towards commercial success may be long and winding. This review discusses the product- and patient-related variables that may pose challenges for the industry and developers both from the scientific and regulatory perspective.
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http://dx.doi.org/10.1007/s11095-018-2436-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5982434PMC
May 2018

Symptomatic Cryofibrinogenemia Following Trauma.

J Clin Rheumatol 2017 Dec;23(8):449-450

Baylor College of MedicineHouston, TX Baylor College of MedicineHouston, TX Baylor College of MedicineHouston, TX; and Texas OncologyHouston, TX.

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http://dx.doi.org/10.1097/RHU.0000000000000590DOI Listing
December 2017

Ethambutol optic neuropathy.

Curr Opin Ophthalmol 2017 Nov;28(6):545-551

aBaylor College of Medicine bDepartment of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital cDepartments of Ophthalmology, Neurology, and Neurosurgery, Weill Cornell Medicine dDepartment of Ophthalmology, UTMB, Galveston, University of Iowa Hospitals and Clinics, Texas A and M College of Medicine eUniversity of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.

Purpose Of Review: We provide a summary of the epidemiology, clinical findings, management and outcomes of ethambutol-induced optic neuropathy (EON). Ethambutol-induced optic neuropathy is a well-known, potentially irreversible, blinding but largely preventable disease. Clinicians should be aware of the importance of patient and physician education as well as timely and appropriate screening.

Recent Findings: Two of the largest epidemiologic studies investigating EON to date showed the prevalence of EON in all patients taking ethambutol to be between 0.7 and 1.29%, a value consistent with previous reports of patients taking the doses recommended by the World Health Organization (WHO). Several studies evaluated the utility of optical coherence tomography (OCT) in screening for EON. These showed decreased retinal nerve fiber layer (RNFL) thickness in patients with clinically significant EON, but mixed results in their ability to detect such changes in patients taking ethambutol without visual symptoms.

Summary: Ethambutol-induced optic neuropathy is a well-known and devastating complication of ethambutol therapy. It may occur in approximately 1% of patients taking ethambutol at the WHO recommended doses, though the risk increases substantially with increased dose. All patients on ethambutol should receive regular screening by an ophthalmologist including formal visual field testing. Visual evoked potentials and OCT may be helpful for EON screening, but more research is needed to clarify their clinical usefulness. Patients who develop signs or symptoms of EON should be referred to the ethambutol-prescribing physician immediately for discontinuation or a reduction in ethambutol dosing.
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http://dx.doi.org/10.1097/ICU.0000000000000416DOI Listing
November 2017

Psychophysiological and Behavioral Responses to a Novel Intruder Threat Task for Children on the Autism Spectrum.

J Autism Dev Disord 2017 Dec;47(12):3704-3713

Brigham Young University, Provo, UT, USA.

We measured skin conductance response (SCR) to escalating levels of a direct social threat from a novel, ecologically-relevant experimental paradigm, the Intruder Threat Task. We simultaneously evaluated the contribution of social symptom severity and behavioral movement. Children with AS group showed less psychophysiological reactivity to social threat than controls across all three phases of the experiment. In the AS group, greater social impairment was significantly associated with reduced SCR. However, movement activity predicted SCR while diagnosis did not. Research and treatment need to account for the complex interplay of emotional reactivity and social behavior in AS. Psychophysiology studies of AS should consider the impact of possible confounds such as movement.
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http://dx.doi.org/10.1007/s10803-017-3195-0DOI Listing
December 2017

Controversies in Establishing Biosimilarity: Extrapolation of Indications and Global Labeling Practices.

BioDrugs 2016 Feb;30(1):1-8

NDA Advisory Services Ltd, Prime House, Challenge Court, Barnett Wood Lane, Leatherhead, Surrey, KT22 7DE, UK.

The principles of establishing biosimilarity are to demonstrate structural and functional similarity to a reference product using the most discriminatory analytical methods. There is still considerable controversy on the scientific basis for extrapolation of indications for biosimilars, which has been strengthened by diverging global regulatory decision making. Closely related to the question of extrapolation is the question of how to communicate the evidence base for authorizing biosimilars to healthcare professionals. In this paper we will consider some of the discussions around extrapolation of indications and the implications of decisions of various regulatory agencies in the world regarding the authorization and labeling of biosimilars.
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http://dx.doi.org/10.1007/s40259-015-0154-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4746210PMC
February 2016

Prognostic value of p16 expression in Epstein-Barr virus-positive nasopharyngeal carcinomas.

Head Neck 2016 04 11;38 Suppl 1:E1459-66. Epub 2015 Nov 11.

Department of Radiation Oncology, MD Anderson Cancer Center, University of Texas, Houston, Texas.

Background: Overexpression of p16 is associated with improved outcomes among patients with oropharyngeal carcinoma. However, its role in the outcomes of patients with nasopharyngeal cancer (NPC) remains unclear.

Methods: Eighty-six patients with NPC treated at MD Anderson Cancer Center from 2000 to 2014 were identified. Epstein-Barr virus (EBV) and human papillomavirus (HPV) status were determined by in situ hybridization (ISH) and p16 by immunohistochemical staining.

Results: EBV positivity was associated with extended overall survival (OS; median, 95.0 vs 44.9 months; p < .004), progression-free survival (PFS; median, 80.4 vs 28.1 months; p < .013), and locoregional control (median, 104.4 vs 65.5 months; p < .043). In patients with EBV-positive tumors, p16 overexpression correlated with improved PFS (median, 106.3 vs 27.1 months; p < .02) and locoregional control (median, 93.6 vs 64.5 months; p < .02).

Conclusion: P16 overexpression is associated with improved PFS and locoregional control in patients with EBV-positive NPC. P16 expression may complement EBV status in predicting treatment outcomes for patients with NPC. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1459-E1466, 2016.
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http://dx.doi.org/10.1002/hed.24258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903429PMC
April 2016

Enhanced decision making and risk avoidance in high-functioning autism spectrum disorder.

Neuropsychology 2014 Mar 11;28(2):222-8. Epub 2013 Nov 11.

Faculty of Medicine, Institute of Neuroscience, Newcastle University.

Objective: Everyday decision making requires integration of a broad range of information from a variety of sources, including cognitive and emotional processes. For individuals with autism spectrum disorder (ASD), everyday decision making can be difficult. The mechanisms that underlie decision making in young people diagnosed with ASD have not been fully explored.

Method: We studied children and young adolescents with autism spectrum disorder (ASD; n = 48) compared with an age- and ability-matched typical control group (CON; n = 54). We evaluated performance and psycho-physiological responsivity during the Iowa Gambling Task (IGT), an affective decision-making task.

Results: ASD participants were superior to control participants on overall performance (p < .05), especially because of significantly better learning in later stages of the task. While both groups showed robust and equal psycho-physiological arousal to disadvantageous decks, the groups differed in their choice of card type, with the CON group choosing more often from the frequent-gain disadvantageous deck, despite occasional large losses; while the ASD group chose prominently from the advantageous decks.

Conclusions: A decision-making style characterized by a drive to avoid potential loss rather than to seek possible reward may help decision making for ASD in some situations, but ultimately hinder functioning in relation to prosocial engagement and other complex situations where gain rather than punishment is the most effective motivating factor.
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http://dx.doi.org/10.1037/neu0000016DOI Listing
March 2014

A potentiated startle study of uncertainty and contextual anxiety in adolescents diagnosed with autism spectrum disorder.

Mol Autism 2013 Sep 4;4(1):31. Epub 2013 Sep 4.

Neuroscience Center, Brigham Young University, S192 ESC, Provo, UT 84602, USA.

Background: Beyond the core symptoms of autism spectrum disorder (ASD), associated symptoms of anxiety can cause substantial impairment for individuals affected by ASD and those who care for them.

Methods: We utilized a potentiated startle paradigm with a puff of air to the neck as the unconditioned stimulus in order to investigate differences between response to cued fear and contextual anxiety among cognitively able adolescents diagnosed with ASD and an age- and IQ-matched typically developing group.

Results: In a threat-modulated startle paradigm, response patterns to neutral, predictable, and unpredictable conditions were comparable across typically developing and ASD youth in terms of startle response magnitude and latency. However, the ASD group showed significantly greater absolute startle responsivity at baseline and throughout the experiment, suggesting possibly enhanced general sensitivity to threatening contexts. The ASD group, but not the control group, demonstrated moderate to strong negative correlations between psychophysiological response to unpredictable threats (uncertainty) and questionnaire measures of generalized anxiety, intolerance of uncertainty, and repetitive behavior.

Conclusions: Our data suggest enhanced general reactivity among the ASD group, possibly reflecting greater sensitivity to the threatening context of the startle paradigm. Associations with the response to uncertainty may help explain shared neurobehavioral mechanisms in ASD and anxiety. This task can provide useful targets for future neuroimaging and genetics studies as well as specific avenues for intervention. We emphasize the importance of further basic and clinical research into links among these important constructs.
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http://dx.doi.org/10.1186/2040-2392-4-31DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844321PMC
September 2013

Assessing immunogenicity of biosimilar therapeutic monoclonal antibodies: regulatory and bioanalytical considerations.

Authors:
Paul Chamberlain

Bioanalysis 2013 Mar;5(5):561-74

NDA Regulatory Advisory Board, NDA Advisory Services Limited, Prime House, Challenge Court, Barnett Wood Lane, Leatherhead, Surrey, KT22 7DE, UK.

This article reflects on methodological limitations for interpretation of relative immunogenicity of biosimilar and reference therapeutic monoclonal antibodies, in emphasizing the relevance of correlation of bioanalytical signals with appropriate clinical end points, and the possible need for post-marketing observational studies to indicate the impact of detected differences in anti-drug antibody incidence and magnitude on sustainability of treatment benefit. Given the current uncertainty regarding the longer term clinical impact of undesirable immunogenicity for reference products, there can be no predefined margin for an acceptable difference based on incidence and magnitude of detected anti-drug antibodies. Any detected differences should be assessed in relation to clinical parameters; and the designation of biosimilarity made with reference to the similarity demonstrated in the directly comparative quality, nonclinical and clinical evaluations. Application of this 'totality of evidence' approach is illustrated for infliximab and adalimumab.
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http://dx.doi.org/10.4155/bio.13.6DOI Listing
March 2013

Root and arbuscular mycorrhizal mycelial interactions with soil microorganisms in lowland tropical forest.

FEMS Microbiol Ecol 2013 Jul 20;85(1):37-50. Epub 2013 Mar 20.

Department of Plant Sciences, University of Cambridge, Cambridge, UK.

Tropical forests have high rates of soil carbon cycling, but little information is available on how roots, arbuscular mycorrhizal fungi (AMF), and free-living microorganisms interact and influence organic matter mineralization in these ecosystems. We used mesh ingrowth cores and isotopic tracers in phospholipid fatty acid biomarkers to investigate the effects of roots and AMF mycelia on (1) microbial community composition, microbial carbon utilization, and hydrolytic enzyme activities for large, potted tropical trees and (2) enzyme activities and litter mass loss in a lowland tropical forest. Under the tropical tree, plant-derived carbon was incorporated predominantly into bacterial groups in both rhizosphere and AMF-only soils. Gram-positive bacteria incorporated additional soil-derived carbon in rhizosphere soils, which also contained the highest microbial biomass. For hydrolytic enzymes, β-glucosidase and N-acetyl β-glucosaminidase activities were highest in rhizosphere soils, while phosphomonoesterase activity was highest in AMF-only soil. In the forest, leaf litter mass loss was increased by the presence of roots, but not by the presence of AMF mycelia only. Root-microbial interactions influenced organic matter cycling, with evidence for rhizosphere priming and accelerated leaf litter decomposition in the presence of roots. Although AMF mycelia alone did not stimulate organic matter mineralization, they were a conduit of carbon to other soil microorganisms.
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http://dx.doi.org/10.1111/1574-6941.12096DOI Listing
July 2013

Ocular physiology and comfort in neophyte subjects fitted with daily disposable silicone hydrogel contact lenses.

Cont Lens Anterior Eye 2013 Jun 30;36(3):118-25. Epub 2012 Dec 30.

Eurolens Research, The University of Manchester, Manchester, United Kingdom.

Purpose: To evaluate the performance of a silicone hydrogel daily disposable lens in neophyte subjects over 12 months.

Methods: Seventy four subjects with no previous contact lens experience were randomised to wear narafilcon A (1 DAY ACUVUE(®) TruEye™) lenses (LW group) or to wear no contact lenses (NLW group) for 12 months. Biomicroscopy (performed by a masked investigator), visual acuity and subjective response scores were recorded at an initial visit and six follow-up visits, in addition to lens fit and surface evaluation for the LW group. Comfort was recorded with SMS messaging.

Results: Fifteen of the LW group discontinued before the end of the study, compared with six of the NLW group. Measured visual acuity was about half a line better for the NLW group as these subjects were provided with their full sphero-cylindrical over-refraction, compared to the LW group in their best spherical corrected contact lenses; subjective scores for vision were similar for the two groups. Bulbar conjunctival hyperaemia, limbal hyperaemia, corneal staining, conjunctival staining and papillary conjunctivitis were clinically equivalent for the two groups whereas conjunctival staining was higher in the LW group. Comfort scores assessed by SMS were equivalent for the LW and NLW groups; there was a measurable improvement in comfort during the first month of wear for the LW group.

Conclusion: This work has demonstrated that modern soft lenses (narafilcon A daily disposable silicone hydrogel lenses) offer an excellent, comfortable form of vision correction, and are able to exhibit minimal alterations to ocular physiology.
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http://dx.doi.org/10.1016/j.clae.2012.12.001DOI Listing
June 2013

Delayed reversal learning and association with repetitive behavior in autism spectrum disorders.

Autism Res 2012 Dec 24;5(6):398-406. Epub 2012 Oct 24.

Department of Psychology, Brigham Young University, Provo, UT 84602, USA.

An important aspect of successful emotion regulation is the ability to adjust emotional responses to changing environmental cues. Difficulties with such adaptation may underlie both marked symptoms of behavioral inflexibility and frequent severe anxiety in the autism spectrum disorders (ASDs). Thirty children and adolescents diagnosed with ASD and 29 age- and intelligence quotient-matched controls completed a reversal learning paradigm following partial reinforcement Pavlovian fear conditioning, using a surprising air puff as the unconditioned stimulus. After initial reversal of cue contingencies, where a previously safe cue now predicted the air puff threat, the control group but not the ASD group responded more strongly to the new threat cue. The ASD group showed evidence for reversal learning only during later trials. Reversal learning in the ASD group was significantly negatively correlated with everyday symptoms of behavioral inflexibility but not with everyday anxiety. Understanding shared associations between inflexibility, anxiety, and autism, with regard both to clinical symptoms and neurobiological mechanisms, can provide important markers for better characterizing the substantial heterogeneity across the autism spectrum.
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http://dx.doi.org/10.1002/aur.1255DOI Listing
December 2012

Congenital toxoplasmosis: continued parasite proliferation in the fetal brain despite maternal immunological control in other tissues.

Clin Infect Dis 2013 Jan 16;56(2):204-8. Epub 2012 Oct 16.

Nuffield Department of Clinical Laboratory Science, Oxford University Hospital, UK.

Background: Congenital toxoplasmosis is a serious condition but little is known of the natural history of parasite development and associated fetal tissue destruction.

Methods: Two cases identified by ultrasound underwent induced abortion at 21 and 30 weeks' gestation. At autopsy, the placenta and fetal organs were examined by histology and immunocytochemistry employing anti-Toxoplasma stage-specific antibodies to confirm diagnosis and also provide information on the stage of parasite development.

Results: In both cases, maternal serology prior to termination showed both specific immunoglobulin M (IgM) and immunoglobulin G (IgG), whereas retrospective analysis of an earlier sample (12-14 weeks' gestation) showed only IgM reactivity consistent with infection occurring in the first trimester. The finding of a number of tissue cysts but few or no tachyzoites within the placenta and fetal adrenal and heart is characteristic of a chronic infection. However, in contrast, there were still areas of the fetal brain with large numbers of actively dividing, tissue-destructive tachyzoites.

Conclusions: These observations show that continued parasite proliferation and tissue destruction can occur within the fetal brain even when there is a marked maternal immune response including maternal IgG. This finding strongly suggests that there may be benefits from treating cases of recently acquired congenital infection to destroy any remaining proliferating parasites located in immunologically protected sites such as the fetal brain.
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http://dx.doi.org/10.1093/cid/cis882DOI Listing
January 2013