Publications by authors named "Richard Allen"

664 Publications

Eyelid Malposition after Blepharoplasty: An Ounce of Prevention.

Semin Plast Surg 2021 May 8;35(2):72-77. Epub 2021 Jun 8.

Department of Ophthalmology, Baylor College of Medicine, Houston, Texas.

Upper and lower eyelid blepharoplasty are common procedures performed to provide a more youthful and rejuvenated appearance. However, this seemingly straightforward procedure may result in lid malpositions, frustrating the patient and surgeon alike, which ultimately require further treatment. We review preoperative assessment pearls to avoid these lid malpositions, as well as options for treating any postoperative complications related to lid position. Many of the techniques discussed in this article, in addition to many other oculoplastic procedures, are available to view in Dr. Richard C. Allen's operative video library at: http://webeye.ophth.uiowa.edu/eyeforum/video/plastics/ .
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http://dx.doi.org/10.1055/s-0041-1727281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186993PMC
May 2021

#OculoplasticsandSocialMedia: a review of social media in oculoplastics and relevant subspecialties.

Orbit 2021 May 27:1-9. Epub 2021 May 27.

Department of Ophthalmology & Visual Sciences, Montefiore Medical Center, Bronx, New York, USA.

The permeation of social media into life almost goes without bounds and medicine is no exception. While social media holds great potential for physicians and medicine, it also comes with concurrent spread of disinformation. This increases the importance of evidence-based information from qualified physicians on social media.Although the definition of social media is broad, in general, it refers to the use of web-based platforms to connect one human to another. In oculoplastic surgery, these relationships can be physician to physician, physician to patient, patient to patient, and vendor to physician. These relationships mostly involve education, social support, and advertising, but can also include research and government advocacy. The purpose of this review is to evaluate the current utilization of social media in oculoplastic surgery and relevant subspecialties.
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http://dx.doi.org/10.1080/01676830.2021.1930064DOI Listing
May 2021

Akathisia and Restless Legs Syndrome: Solving the Dopaminergic Paradox.

Sleep Med Clin 2021 Jun 10;16(2):249-267. Epub 2021 Apr 10.

Department of Neurology, Johns Hopkins University, Johns Hopkins Bayview Medical Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA.

Akathisia is an urgent need to move that is associated with treatment with dopamine receptor blocking agents (DRBAs) and with restless legs syndrome (RLS). The pathogenetic mechanism of akathisia has not been resolved. This article proposes that it involves an increased presynaptic dopaminergic transmission in the ventral striatum and concomitant strong activation of postsynaptic dopamine D receptors, which form complexes (heteromers) with dopamine D and adenosine A receptors. It also proposes that in DRBA-induced akathisia, increased dopamine release depends on inactivation of autoreceptors, whereas in RLS it depends on a brain iron deficiency-induced down-regulation of striatal presynaptic A receptors.
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http://dx.doi.org/10.1016/j.jsmc.2021.02.012DOI Listing
June 2021

Modeling is data driven: Use it for successful virtual patient generation.

CPT Pharmacometrics Syst Pharmacol 2021 May 2;10(5):393-394. Epub 2021 May 2.

Quantitative Systems Pharmacology, Early Clinical Development, Pfizer Worldwide Research Development and Medical, Cambridge, Massachusetts, USA.

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http://dx.doi.org/10.1002/psp4.12630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129709PMC
May 2021

The effect of value on long-term associative memory.

Q J Exp Psychol (Hove) 2021 May 15:17470218211014439. Epub 2021 May 15.

School of Psychology, University of Leeds, Leeds, UK.

Items with high value are often remembered better than those with low value. It is not clear, however, whether this value effect extends to the binding of associative details (e.g., word colour) in episodic memory. Here, we explored whether value enhances memory for associative information in two different scenarios that might support a more effective process of binding between identity and colour. Experiment 1 examined incidental binding between item and colour using coloured images of familiar objects, whereas Experiment 2 examined intentional learning of word colour. In both experiments, increasing value led to improvements in memory for both item and colour, and these effects persisted after approximately 24 hr. Experiment 3a and Experiment 3b replicated the value effect on intentional word-colour memory from Experiment 2 while also demonstrating this effect to be less reliable when word colour is incidental to the encoding phase. Thus, value-directed prioritisation can facilitate episodic associative memory when conditions for binding are optimised through the use of appropriate to-be remembered materials and encoding conditions.
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http://dx.doi.org/10.1177/17470218211014439DOI Listing
May 2021

Bilateral orbital inflammation in a 6-month old with SARS-CoV-2 infection.

Orbit 2021 Apr 19:1-4. Epub 2021 Apr 19.

Department of Ophthalmology, Baylor College of Medicine, Houston, Texas, USA.

A 6-month-old female presented with bilateral periorbital edema for 7 days. Laboratory testing was significant for active SARS-CoV-2 infection. Neuroimaging demonstrated soft tissue changes within the bilateral orbits and enlargement of the bilateral lacrimal glands. Although the patient initially improved with corticosteroid treatment, she later returned with recurrent left periorbital and eyelid edema. Orbital biopsy was performed and demonstrated findings in the lacrimal gland and the adjacent fibroconnective tissues that are similar to those of prior lung specimens seen in SARS-CoV-2 patients. Final diagnosis was bilateral orbital inflammation with features presumed secondary to SARS-CoV-2 infection. To the best of our knowledge, this is one of the first reports to document bilateral orbital inflammation as a sign of SARS-CoV-2 infection in the pediatric population with the associated pathological findings.
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http://dx.doi.org/10.1080/01676830.2021.1914670DOI Listing
April 2021

We need to do better: A systematic review and meta-analysis of diagnostic test accuracy of restless legs syndrome screening instruments.

Sleep Med Rev 2021 Mar 13;58:101461. Epub 2021 Mar 13.

Departments of Psychiatry and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address:

This systematic review and meta-analysis evaluated the diagnostic accuracy of screening instruments for restless legs syndrome (RLS) and reports sensitivity, specificity, positive (PPV) and negative predictive values (NPV). Searches for primary studies were conducted in electronic databases. Of the 1541 citations identified, 52 were included in the meta-analysis. The methodological quality of each study was evaluated using QUADAS-2. Only 14 studies assessed the reference standard in all participants or in all screen-positives and a selection of screen-negatives. Bivariate meta-analysis of these 14 studies estimated median sensitivity to be 0.88 (0.72-0.96) and specificity 0.90 (0.84-0.93); based on a population prevalence of 5%, the calculated PPV was 0.31 (0.27-0.34). For all 52 studies, with either full or partial verification of RLS status, we constructed best-case scenario sensitivities and specificities at pre-defined levels of prevalence: across all samples, when prevalence is 5%, the median best-case scenario PPV is 0.48 with significant between-study heterogeneity. No RLS screening instruments can currently be recommended for use without an expert clinical interview in epidemiological studies. For conditions with statistically low prevalence such as RLS, the specificity, not the sensitivity, of a screening instrument determines true prevalence. Therefore, future instruments should maximize specificity. We provide guidelines on RLS ascertainment in epidemiological studies that requires a two-step process with clinical interview following a screening test, and given the poor reporting quality of many RLS epidemiological studies, we include an RLS reporting checklist.
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http://dx.doi.org/10.1016/j.smrv.2021.101461DOI Listing
March 2021

Restless legs syndrome among subjects having chronic liver disease: A systematic review and meta-analysis.

Sleep Med Rev 2021 Mar 11;58:101463. Epub 2021 Mar 11.

Department of Neurology, John Hopkins University, Baltimore, MD, USA.

Sleep disturbances are commonly reported in patients with chronic liver disease (CLD). Changes in quality of sleep in patients with CLD could be related to multiple factors viz., elevated levels of tryptophan, histamine, and increased turnover of dopamine in caudate-putamen and cingulate cortex. Also, iron metabolism disturbances are reported in patients with CLD. These changes may result in restless legs syndrome (RLS) that worsens sleep-quality. There have been reports suggesting an increased prevalence of RLS among patients with CLD. Literature was searched in PubMed, EMBASE, and Google Scholar. A total of twenty-two relevant articles were found. Out of these, nine studies have assessed the prevalence of RLS among patients with chronic liver disease or cirrhosis in the clinical population. Population prevalence reported from various studies was used to calculate odds ratio. Having included studies using various methods for diagnosis (clinical as well as questionnaires) pooled odds-ratio for the RLS was 8.62. It remains unaffected by study-method, gender, age, and geographical-area. However, studies using clinical diagnosis for RLS had lower odds compared to questionnaire based diagnosis. Studies varied with regards to diagnostic methods, age, gender, etiology, and severity of liver dysfunction. The severity and etiology of CLD and biochemical correlate of CLD were not found to be associated with RLS. Possible pathophysiological mechanisms are discussed for the occurrence of RLS in this population. In conclusion, the prevalence of RLS is higher among patients with CLD, however, the correlates are unknown.
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http://dx.doi.org/10.1016/j.smrv.2021.101463DOI Listing
March 2021

Identification of a missense variant in SPDL1 associated with idiopathic pulmonary fibrosis.

Commun Biol 2021 Mar 23;4(1):392. Epub 2021 Mar 23.

Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.

Idiopathic pulmonary fibrosis (IPF) is a fatal disorder characterised by progressive, destructive lung scarring. Despite substantial progress, the genetic determinants of this disease remain incompletely defined. Using whole genome and whole exome sequencing data from 752 individuals with sporadic IPF and 119,055 UK Biobank controls, we performed a variant-level exome-wide association study (ExWAS) and gene-level collapsing analyses. Our variant-level analysis revealed a novel association between a rare missense variant in SPDL1 and IPF (NM_017785.5:g.169588475 G > A p.Arg20Gln; p = 2.4 × 10, odds ratio = 2.87, 95% confidence interval: 2.03-4.07). This signal was independently replicated in the FinnGen cohort, which contains 1028 cases and 196,986 controls (combined p = 2.2 × 10), firmly associating this variant as an IPF risk allele. SPDL1 encodes Spindly, a protein involved in mitotic checkpoint signalling during cell division that has not been previously described in fibrosis. To the best of our knowledge, these results highlight a novel mechanism underlying IPF, providing the potential for new therapeutic discoveries in a disease of great unmet need.
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http://dx.doi.org/10.1038/s42003-021-01910-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988141PMC
March 2021

Pharmacologic inhibition of ketohexokinase prevents fructose-induced metabolic dysfunction.

Mol Metab 2021 Jun 3;48:101196. Epub 2021 Mar 3.

Internal Medicine Research Unit, Pfizer Worldwide Research, Development, and Medical, Cambridge, MA 02139 USA. Electronic address:

Objective: Recent studies suggest that excess dietary fructose contributes to metabolic dysfunction by promoting insulin resistance, de novo lipogenesis (DNL), and hepatic steatosis, thereby increasing the risk of obesity, type 2 diabetes (T2D), non-alcoholic steatohepatitis (NASH), and related comorbidities. Whether this metabolic dysfunction is driven by the excess dietary calories contained in fructose or whether fructose catabolism itself is uniquely pathogenic remains controversial. We sought to test whether a small molecule inhibitor of the primary fructose metabolizing enzyme ketohexokinase (KHK) can ameliorate the metabolic effects of fructose.

Methods: The KHK inhibitor PF-06835919 was used to block fructose metabolism in primary hepatocytes and Sprague Dawley rats fed either a high-fructose diet (30% fructose kcal/g) or a diet reflecting the average macronutrient dietary content of an American diet (AD) (7.5% fructose kcal/g). The effects of fructose consumption and KHK inhibition on hepatic steatosis, insulin resistance, and hyperlipidemia were evaluated, along with the activation of DNL and the enzymes that regulate lipid synthesis. A metabolomic analysis was performed to confirm KHK inhibition and understand metabolite changes in response to fructose metabolism in vitro and in vivo. Additionally, the effects of administering a single ascending dose of PF-06835919 on fructose metabolism markers in healthy human study participants were assessed in a randomized placebo-controlled phase 1 study.

Results: Inhibition of KHK in rats prevented hyperinsulinemia and hypertriglyceridemia from fructose feeding. Supraphysiologic levels of dietary fructose were not necessary to cause metabolic dysfunction as rats fed the American diet developed hyperinsulinemia, hypertriglyceridemia, and hepatic steatosis, which were all reversed by KHK inhibition. Reversal of the metabolic effects of fructose coincided with reductions in DNL and inactivation of the lipogenic transcription factor carbohydrate response element-binding protein (ChREBP). We report that administering single oral doses of PF-06835919 was safe and well tolerated in healthy study participants and dose-dependently increased plasma fructose indicative of KHK inhibition.

Conclusions: Fructose consumption in rats promoted features of metabolic dysfunction seen in metabolic diseases such as T2D and NASH, including insulin resistance, hypertriglyceridemia, and hepatic steatosis, which were reversed by KHK inhibition.
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http://dx.doi.org/10.1016/j.molmet.2021.101196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050029PMC
June 2021

Vitamin D and bacterial pneumonias: the question of causality.

Thorax 2021 Mar 2. Epub 2021 Mar 2.

Department of Health Sciences, University of Leicester, Leicester, UK

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http://dx.doi.org/10.1136/thoraxjnl-2020-216375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070627PMC
March 2021

Bilateral acquired nasolacrimal duct obstruction secondary to amyloidosis in a 15-year-old.

J AAPOS 2021 Apr 27;25(2):126-128. Epub 2021 Feb 27.

Department of Ophthalmology, Baylor College of Medicine, Houston, Texas; Department of Ophthalmology, Texas Children's Hospital, Houston, Texas. Electronic address:

A 15-year-old boy who presented with a 1-week history of increasing erythema, edema, and tenderness of the right upper and lower eyelids was found to have acquired nasolacrimal duct obstruction (NLDO) secondary to primary amyloidosis. To our knowledge, this is the youngest case of bilateral NLDO secondary to primary amyloidosis (biopsy proven for right NLDO and presumed for left NLDO) reported in the literature. This case highlights the importance of lacrimal sac biopsy in patients with acquired NLDO of unclear etiology. Given the prevalence of the primary amyloidosis subtype in cases of ocular or adnexal amyloidosis, patients should undergo immediate workup for systemic disease.
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http://dx.doi.org/10.1016/j.jaapos.2020.11.011DOI Listing
April 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

Developing a biomarker for restless leg syndrome using genome wide DNA methylation data.

Sleep Med 2021 02 21;78:120-127. Epub 2020 Dec 21.

The Royal's Institute of Mental Health Research, University of Ottawa, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa Ontario Canada; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Mental Health, Bloomberg School of Public Health, Baltimore, MD, USA. Electronic address:

This study reports on an epigenetic biomarker for restless leg syndrome (RLS) developed using whole genome DNA methylation data. Lymphocyte-derived DNA methylation was examined in 15 subjects with and without RLS (discovery cohort). T-tests and linear regressions were used followed by a principal component analysis (PCA). The principal component model from the discovery cohort was used to predict RLS status in a peripheral blood (N = 24; including 12 cases and 12 controls) and a post-mortem neural tissue (N = 71; including 36 cases and 35 controls) replication cohort as well as iron deficiency anemia status in a publicly available dataset (N = 71, 59 cases with iron deficiency anemia, 12 controls). Using receiver-operating characteristic analysis the optimum biomarker model - that included 49 probes - predicted RLS status in the blood-based replication cohort with an area under the curve (AUC) of 87.5% (confidence interval = 71.9%-100%). In the neural tissue samples, the model predicted RLS status with an AUC of 73.4% (confidence interval = 61.5%-85.3%). An AUC of 83% was found for predictions of iron deficiency anemia. Thus, the blood-based biomarker model reported here and built with epigenome-wide data showed reasonable replicability in lymphocytes and neural tissue samples. A limitation of this study is that we could not determine the metabolic or neurobiological pathways linking epigenetic changes with RLS. Further research is needed to fine-tune this model for prospective predictions of RLS and to enable translation for clinical use.
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http://dx.doi.org/10.1016/j.sleep.2020.12.017DOI Listing
February 2021

Consensus Guidelines on Rodent Models of Restless Legs Syndrome.

Mov Disord 2021 03 31;36(3):558-569. Epub 2020 Dec 31.

Sleep Medicine Unit, Regional Hospital of Lugano, Neurocenter of Southern Switzerland, Lugano, Switzerland.

Restless legs syndrome (RLS) is a chronic sensorimotor disorder diagnosed by clinical symptoms. It is challenging to translate the diagnostic self-reported features of RLS to animals. To help researchers design their experiments, a task force was convened to develop consensus guidelines for experimental readouts in RLS animal models. The RLS clinical diagnostic criteria were used as a starting point. After soliciting additional important clinical features of RLS, a consensus set of methods and outcome measures intent on capturing these features-in the absence of a face-to-face interview-was generated and subsequently prioritized by the task force. These were, in turn, translated into corresponding methods and outcome measures for research on laboratory rats and mice and used to generate the final recommendations. The task force recommended activity monitoring and polysomnography as principal tools in assessing RLS-like behavior in rodents. Data derived from these methods were determined to be the preferred surrogate measures for the urge to move, the principal defining feature of RLS. The same tools may be used to objectively demonstrate sleep-state features highly associated with RLS, such as sleep disturbance and number and periodicity of limb movements. Pharmacological challenges and dietary or other manipulations that affect iron availability are desirable to aggravate or improve RLS-like behavior and lend greater confidence that the animal model being proffered replicates key clinical features of RLS. These guidelines provide the first consensus experimental framework for researchers to use when developing new rodent models of RLS. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28401DOI Listing
March 2021

Nighttime Agitation in Persons with Dementia as a Manifestation of Restless Legs Syndrome.

J Am Med Dir Assoc 2020 Dec 18. Epub 2020 Dec 18.

Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.

Objectives: Nighttime agitation or "sundowning" is challenging for clinicians and caregivers to manage in older adults in the dementia stage of Alzheimer's disease (AD-D). Our research previously revealed that nighttime agitation might be a manifestation of restless legs syndrome (RLS). The current study aims to describe the characteristics of older adults with AD-D, nighttime agitation, and RLS, and to evaluate sleep disturbance and iron status in relation to nighttime agitation severity.

Design: An observational study with baseline descriptive and correlational data from a clinical trial.

Setting And Participants: Long-term care (n = 69) and independent living (n = 7); age 82.91 ± 9.46 years, with AD-D, nighttime agitation, and RLS.

Measurements: Trained observers counted nighttime agitation behaviors. Independent variables were age; cognition measured by the Mini-Mental State Examination; minutes slept from actigraphy; transferrin saturation percentage (TS%) and transferrin from fasting blood samples; and illness severity using the Cumulative Illness Rating Scale for Geriatrics. Bivariate and multivariable linear regression models were generated.

Results: In the multivariable model, sleep minutes (P = .002) and TS% (P = .003) were negatively associated with frequency of nighttime agitation behaviors, and they explained 20% of the variance. Seventy-nine percent received 1 or more medications that worsen RLS symptoms, such as antihistamines and serotonin reuptake inhibitors.

Conclusions And Implications: We encourage clinicians to consider nighttime agitation as a manifestation of RLS. Treatment of iron deficiency indicated by low TS% and deprescribing medications that exacerbate RLS may decrease nighttime agitation, improve sleep, and enhance quality of life in older adults with AD-D.
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http://dx.doi.org/10.1016/j.jamda.2020.11.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211902PMC
December 2020

Health-Related Quality of Life in People Across the Spectrum of CKD.

Kidney Int Rep 2020 Dec 3;5(12):2264-2274. Epub 2020 Oct 3.

College of Medicine and Public Health, Flinders University, Adelaide, Australia.

Introduction: People with chronic kidney disease (CKD) experience reduced quality of life (QoL) because of the high symptom and treatment burden. Limited data exist on the factors associated with overall and domain-specific QoL across all CKD stages.

Methods: Using data from a prospective, multinational study (Australia, New Zealand, Canada, and Spain) in 1696 participants with CKD, we measured overall and domain-specific QoL (pain, self-care, activity, mobility, anxiety/depression) using the EuroQoL, 5 dimension, 3 level. Multivariable linear regression and logistic modeling were used to determine factors associated with overall and domain-specific QoL.

Results: QoL for patients with CKD stages 3 to 5 (n = 787; mean, 0.81; SD, 0.20) was higher than in patients on dialysis (n = 415; mean, 0.76; SD, 0.24) but lower than in kidney transplant recipients (n = 494; mean, 0.84; SD, 0.21). Factors associated with reduced overall QoL (β [95% confidence intervals]) included being on dialysis (compared with CKD stages 3-5: -0.06 [-0.08 to -0.03]), female sex (-0.03 [-0.05 to -0.006]), lower educational attainment (- 0.04 [-0.06 to -0.02), lacking a partner (-0.04 [-0.06 to -0.02]), having diabetes (-0.05 [-0.07 to -0.02]), history of stroke (-0.09 [-0.13 to -0.05]), cardiovascular disease (-0.06 [-0.08 to -0.03]), and cancer (-0.03 [-0.06 to -0.009]). Pain (43%) and anxiety/depression (30%) were the most commonly affected domains, with dialysis patients reporting decrements in all 5 domains. Predictors for domain-specific QoL included being on dialysis, presence of comorbidities, lower education, female sex, and lack of a partner.

Conclusions: Being on dialysis, women with CKD, those with multiple comorbidities, lack of a partner, and lower educational attainment were associated with lower QoL across all stages of CKD.
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http://dx.doi.org/10.1016/j.ekir.2020.09.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710842PMC
December 2020

Macrophages Mediate the Antitumor Effects of the Oncolytic Virus HSV1716 in Mammary Tumors.

Mol Cancer Ther 2021 03 9;20(3):589-601. Epub 2020 Dec 9.

Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom.

Oncolytic viruses (OV) have been shown to activate the antitumor functions of specific immune cells like T cells. Here, we show OV can also reprogram tumor-associated macrophage (TAM) to a less immunosuppressive phenotype. Syngeneic, immunocompetent mouse models of primary breast cancer were established using PyMT-TS1, 4T1, and E0771 cell lines, and a metastatic model of breast cancer was established using the 4T1 cell line. Tumor growth and overall survival was assessed following intravenous administration of the OV, HSV1716 (a modified herpes simplex virus). Infiltration and function of various immune effector cells was assessed by NanoString, flow cytometry of dispersed tumors, and immunofluorescence analysis of tumor sections. HSV1716 administration led to marked tumor shrinkage in primary mammary tumors and a decrease in metastases. This was associated with a significant increase in the recruitment/activation of cytotoxic T cells, a reduction in the presence of regulatory T cells and the reprograming of TAMs towards a pro-inflammatory, less immunosuppressive phenotype. These findings were supported by data demonstrating that human monocyte-derived macrophages host HSV1716 replication, and that this led to immunogenic macrophage lysis. These events were dependent on macrophage expression of proliferating cell nuclear antigen (PCNA). Finally, the antitumor effect of OV was markedly diminished when TAMs were depleted using clodronate liposomes. Together, our results show that TAMs play an essential role in support of the tumoricidal effect of the OV, HSV1716-they both host viral replication via a novel, PCNA-dependent mechanism and are reprogramed to express a less immunosuppressive phenotype.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0748DOI Listing
March 2021

Comparing motor imagery and verbal rehearsal strategies in children's ability to follow spoken instructions.

J Exp Child Psychol 2021 Mar 2;203:105033. Epub 2020 Dec 2.

Neuropsychology and Applied Cognitive Neuroscience Laboratory, CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China; Department of Psychology, University of Chinese Academy of Sciences, Beijing 100049, China.

The ability to follow spoken instructions is critical for children's learning in school and relies on the storage and processing of information in working memory. This study compared the effects of two encoding strategies (motor imagery and verbal rehearsal) on children's ability to follow spoken instructions in a working memory paradigm. A total of 146 children aged 7-12 years completed an instruction span task. In this task, children listened to a series of action-object commands and encoded them by either motor imagery or verbal rehearsal. They then attempted to recall the sequence in serial order by either enacted recall or verbal recall. Overall, children's ability to follow spoken instructions increased with age. In all age groups, children showed superior recall of instructions when they imagined the actions compared with verbal rehearsal of the actions during encoding, and this benefit of motor imagery was similar for verbal recall and enacted recall. Younger children reported motor imagery as more helpful than verbal rehearsal for remembering instructions, whereas older children considered verbal rehearsal as more useful. The study provides novel evidence for motor imagery as a superior strategy (relative to verbal rehearsal) for remembering spoken instructions in school-age children.
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http://dx.doi.org/10.1016/j.jecp.2020.105033DOI Listing
March 2021

Following Instructions in Working Memory: Do Older Adults Show the Enactment Advantage?

J Gerontol B Psychol Sci Soc Sci 2021 Mar;76(4):703-710

School of Psychology, University of Leeds, Leeds, UK.

Objectives: In young adults, the ability to verbally recall instructions in working memory is enhanced if the sequences are physically enacted by the participant (self-enactment) or the experimenter (demonstration) during encoding. Here we examine the effects of self-enactment and demonstration at encoding on working memory performance in older and younger adults.

Method: Fifty young (18-23 years) and 40 older (60-89 years) adults listened to sequences of novel action-object pairs before verbally recalling them in the correct order. There were three different encoding conditions: spoken only, spoken + demonstration, and spoken + self-enactment. We included two different levels of difficulty to investigate whether task complexity moderated the effect of encoding condition and whether this differed between age groups.

Results: Relative to the spoken only condition, demonstration significantly improved young and older adults' serial recall performance, but self-enactment only enhanced performance in the young adults, and this boost was smaller than the one gained through demonstration.

Discussion: Our findings suggest that additional spatial-motoric information is beneficial for older adults when the actions are demonstrated to them, but not when the individual must enact the instructions themselves.
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http://dx.doi.org/10.1093/geronb/gbaa214DOI Listing
March 2021

Recurrent upper eyelid trachomatous entropion repair: long-term efficacy of a five-step approach.

Eye (Lond) 2020 Nov 24. Epub 2020 Nov 24.

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

Purpose: To describe the lid characteristics of recurrent upper eyelid trachomatous entropion and to report the long-term outcomes of a five-step surgical approach based on the principles of upper eyelid crease lamellar splitting and retractor release with redirection.

Subjects And Methods: Retrospective case review of adult patients with recurrent upper eyelid trachomatous entropion who had undergone surgical correction using the five-step surgical technique between March 2014 and March 2018. Cases with primary entropion and/or <2 years of follow-up were excluded from this series.

Main Outcome Measures: Eyelid deformities (type of trichiasis, anterior lamellar laxity, lid margin abnormality, lid retraction and lagophthalmos), recurrence of entropion and trichiasis, cosmetic satisfaction, and surgical complications.

Results: Forty-two upper eyelids in 33 patients met inclusion criteria. Preoperative anterior lamellar laxity was present in 36 eyelids (85.7%), lid retraction in 31 eyelids (73.8%) with a mean preoperative MRD1 of 6.48 ± 1.1 mm, atrophic tarsus in 28 eyelids (66.7%), lid margin notching in 22 eyelids (52.4%), and lagophthalmos in 15 eyelids (35.7%). The surgical success rate was 92.9% (95% CI 0.805-0.985). There was no documented recurrence of entropion over a mean follow-up period of 31.79 months. Postoperative trichiasis without entropion occurred in three eyelids, which required repeat epilation.

Conclusions: The five step-approach based on the principles of lamellar splitting is effective in correction of recurrent trachomatous entropion with long-term stability. The procedure addresses the fundamental changes frequently seen in recurrent cases, in particular anterior lamellar laxity, scarred shortened posterior lamella, and trichiasis.
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http://dx.doi.org/10.1038/s41433-020-01306-yDOI Listing
November 2020

A Prototype QSP Model of the Immune Response to SARS-CoV-2 for Community Development.

CPT Pharmacometrics Syst Pharmacol 2021 01 21;10(1):18-29. Epub 2020 Dec 21.

Early Clinical Development, Pfizer Worldwide Research, Development and Medical, Cambridge, Massachusetts, USA.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic requires the rapid development of efficacious treatments for patients with life-threatening coronavirus disease 2019 (COVID-19). Quantitative systems pharmacology (QSP) models are mathematical representations of pathophysiology for simulating and predicting the effects of existing or putative therapies. The application of model-based approaches, including QSP, have accelerated the development of some novel therapeutics. Nevertheless, the development of disease-scale mechanistic models can be a slow process, often taking years to be validated and considered mature. Furthermore, emerging data may make any QSP model quickly obsolete. We present a prototype QSP model to facilitate further development by the scientific community. The model accounts for the interactions between viral dynamics, the major host immune response mediators and tissue damage and regeneration. The immune response is determined by viral activation of innate and adaptive immune processes that regulate viral clearance and cell damage. The prototype model captures two physiologically relevant outcomes following infection: a "healthy" immune response that appropriately defends against the virus, and an uncontrolled alveolar inflammatory response that is characteristic of acute respiratory distress syndrome. We aim to significantly shorten the typical QSP model development and validation timeline by encouraging community use, testing, and refinement of this prototype model. It is our expectation that the model will be further advanced in an open science approach (i.e., by multiple contributions toward a validated quantitative platform in an open forum), with the ultimate goal of informing and accelerating the development of safe and effective treatment options for patients.
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http://dx.doi.org/10.1002/psp4.12574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753647PMC
January 2021

Telomere length and risk of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease: a mendelian randomisation study.

Lancet Respir Med 2021 03 13;9(3):285-294. Epub 2020 Nov 13.

Institute of Biomedical & Clinical Science, College of Medicine & Health, University of Exeter, Exeter, UK; Exeter Patients in Collaboration for PF, Exeter, UK. Electronic address:

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease accounting for 1% of UK deaths. In the familial form of pulmonary fibrosis, causal genes have been identified in about 30% of cases, and a majority of these causal genes are associated with telomere maintenance. Prematurely shortened leukocyte telomere length is associated with IPF and chronic obstructive pulmonary disease (COPD), a disease with similar demographics and shared risk factors. Using mendelian randomisation, we investigated evidence supporting a causal role for short telomeres in IPF and COPD.

Methods: Mendelian randomisation inference of telomere length causality was done for IPF (up to 1369 cases) and COPD (13 538 cases) against 435 866 controls of European ancestry in UK Biobank. Polygenic risk scores were calculated and two-sample mendelian randomisation analyses were done using seven genetic variants previously associated with telomere length, with replication analysis in an IPF cohort (2668 cases vs 8591 controls) and COPD cohort (15 256 cases vs 47 936 controls).

Findings: In the UK Biobank, a genetically instrumented one-SD shorter telomere length was associated with higher odds of IPF (odds ratio [OR] 4·19, 95% CI 2·33-7·55; p=0·0031) but not COPD (1·07, 0·88-1·30; p=0·51). Similarly, an association was found in the IPF replication cohort (12·3, 5·05-30·1; p=0·0015) and not in the COPD replication cohort (1·04, 0·71-1·53; p=0·83). Meta-analysis of the two-sample mendelian randomisation results provided evidence inferring that shorter telomeres cause IPF (5·81 higher odds of IPF, 95% CI 3·56-9·50; p=2·19 × 10). There was no evidence to infer that telomere length caused COPD (OR 1·07, 95% CI 0·90-1·27; p=0·46).

Interpretation: Cellular senescence is hypothesised as a major driving force in IPF and COPD; telomere shortening might be a contributory factor in IPF, suggesting divergent mechanisms in COPD. Defining a key role for telomere shortening enables greater focus in telomere-related diagnostics, treatments, and the search for a cure in IPF. Investigation of therapies that improve telomere length is warranted.

Funding: Medical Research Council.
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http://dx.doi.org/10.1016/S2213-2600(20)30364-7DOI Listing
March 2021

Can valuable information be prioritized in verbal working memory?

J Exp Psychol Learn Mem Cogn 2020 Nov 2. Epub 2020 Nov 2.

School of Psychology, University of Leeds.

Though there is substantial evidence that individuals can prioritize more valuable information in visual working memory (WM), little research has examined this in the verbal domain. Four experiments were conducted to investigate this and the conditions under which effects emerge. In each experiment, participants listened to digit sequences and then attempted to recall them in the correct order. At the start of each block, participants were either told that all items were of equal value, or that an item at a particular serial position was worth more points. Recall was enhanced for these higher value items (Experiment 1a), a finding that was replicated while rejecting an alternative account based on distinctiveness (Experiment 1b). Thus, valuable information can be prioritized in verbal WM. Two further experiments investigated whether these boosts remained when participants completed a simple concurrent task disrupting verbal rehearsal (Experiment 2), or a complex concurrent task disrupting verbal rehearsal and executive resources (Experiment 3). Under simple concurrent task conditions, prioritization boosts were observed, but with increased costs to the less valuable items. Prioritization effects were also observed under complex concurrent task conditions, although this was accompanied by chance-level performance at most of the less valuable positions. A substantial recency advantage was also observed for the final item in each sequence, across all conditions. Taken together, this indicates that individuals can prioritize valuable information in verbal WM even when rehearsal and executive resources are disrupted, though they do so by neglecting or abandoning other items in the sequence. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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http://dx.doi.org/10.1037/xlm0000979DOI Listing
November 2020

Paediatric kidney transplants from donors aged 1 year and under: an analysis of the Australian and New Zealand Dialysis and Transplant Registry from 1963 to 2018.

Transpl Int 2021 Jan 9;34(1):118-126. Epub 2020 Nov 9.

National Pancreas Transplant Unit, Westmead Hospital, Sydney, NSW, Australia.

Kidneys from very small donors have the potential to significantly expand the donor pool. We describe the collective experience of transplantation using kidneys from donors aged ≤1 year in Australian and New Zealand. The ANZDATA registry was analysed on all deceased donor kidney transplants from donors aged ≤1 year. We compared recipient characteristics and outcomes between 1963-1999 and 2000-2018. From 1963 to 1999, 16 transplants were performed [9 (56%) adults, 7 (44%) children]. Death-censored graft survival was 50% and 43% at 1 and 5 years, respectively. Patient survival was 90% and 87% at 1 and 5 years, respectively. From 2000 to 2018, 26 transplants were performed [25 (96%) adults, 1 (4%) children]. Mean creatinine was 73 µmol/l ±49.1 at 5 years. Death-censored graft survival was 85% at 1 and 5 years. Patient survival was 100% at 1 and 5 years. Thrombosis was the cause of graft loss in 12% of recipients in the first era from 1963 to 1999, and 8% of recipients in the second era from 2000 to 2018. We advocate the judicious use of these small paediatric grafts from donors ≤1 year old. Optimal selection of donor and recipients may lead to greater acceptance and success of transplantation from very young donors.
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http://dx.doi.org/10.1111/tri.13772DOI Listing
January 2021

Primary Lacrimal Gland Oncocytoma Associated With Hypervascularity: A Case Report With Imaging and Immunohistochemical Characterization.

Ophthalmic Plast Reconstr Surg 2021 May-Jun 01;37(3S):S128-S130

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

Oncocytoma is a rare benign neoplasm with few cases reported to involve the orbit. When affecting the orbit, oncocytomas have very slow growth and often evade early diagnosis. The diagnostic evaluation of these orbital tumors is not fully understood. The authors present a case of a benign oncocytoma arising in the lacrimal gland associated with significant vascularity and intraoperative bleeding. The authors provide immunohistochemical analysis of this rare orbital tumor and insights in surgical planning.
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http://dx.doi.org/10.1097/IOP.0000000000001792DOI Listing
May 2021

Rapidly Enlarging Hidradenoma of the Eyelid.

Ophthalmic Plast Reconstr Surg 2021 May-Jun 01;37(3S):S149-S151

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

Hidradenoma is a rare benign neoplasm, with few cases reported to involve the eyelid. When affecting the eyelid, hidradenomas may mimic other benign or malignant lesions. Rarely, a benign hidradenoma may transform into a malignant hidradenoma and metastasize. The authors present a case of a benign hidradenoma arising from the eyelid, presenting with rapid growth, ulceration, and bleeding, suggestive of a malignant lesion.
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http://dx.doi.org/10.1097/IOP.0000000000001828DOI Listing
May 2021

Nighttime Agitation and Restless Legs Syndrome in Persons With Alzheimer's Disease: Study Protocol for a Double-Blind, Placebo-Controlled, Randomized Trial (NightRest).

Res Gerontol Nurs 2020 11 24;13(6):280-288. Epub 2020 Sep 24.

Nighttime agitation is a prevalent symptom in persons with Alzheimer's disease (AD). Effective treatments are absent due to our limited knowledge of its etiology. We hypothesized that restless legs syndrome (RLS), a common neurological sensorimotor disorder of uncomfortable leg sensations that appear at night and interfere with sleep, might be a cause for nighttime agitation in persons with AD. RLS is infrequently identified in persons with AD because traditional diagnosis is dependent on patients answering complex questions about their symptoms. With a validated observational tool for RLS diagnosis, the Behavioral Indicators Test-Restless Legs, we aim to diagnose RLS and determine the effect of gabapentin enacarbil (GEn) compared to placebo on nighttime agitation, sleep, antipsychotic medications, and the mechanism for these effects. We hypothesize that frequency of RLS behaviors will mediate the relationship between GEn and nighttime agitation. This study is an 8-week, double-blind, placebo-controlled, randomized pilot clinical trial, followed by an 8-week open-label trial, that is being conducted in long-term care settings and private homes. The results of this study may shift, personalize, and improve standards of care for treatment of nighttime agitation; reduce aggression and other nighttime agitation behaviors; and improve sleep.

Targets: Persons with AD with nighttime agitation potentially caused by RLS.

Intervention Description: Diagnose RLS and determine the effect of GEn.

Mechanisms Of Action: The frequency of RLS behaviors will mediate the relationship between GEn and nighttime agitation.

Outcomes: Determine the effect of GEn on nighttime agitation, sleep, and antipsychotic medications.

Trial Registration: ClinicalTrials.gov Identifier: NCT03082755 (Date of registration March 6, 2017). [Research in Gerontological Nursing, 13(6), 280-288.].
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http://dx.doi.org/10.3928/19404921-20200918-01DOI Listing
November 2020