Publications by authors named "David Simpson"

620 Publications

Zanubrutinib monotherapy in relapsed/refractory mantle cell lymphoma: a pooled analysis of two clinical trials.

J Hematol Oncol 2021 Oct 14;14(1):167. Epub 2021 Oct 14.

Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450003, China.

Mantle cell lymphoma (MCL) is a mature B-cell neoplasm with a high initial response rate followed almost invariably by relapse. Here we report the pooled data from 2 studies, BGB-3111-AU-003 and BGB-3111-206, to explore the efficacy of zanubrutinib monotherapy in relapsed/refractory (R/R) MCL. A total of 112 patients were included. Median follow-up durations were 24.7 and 24.9 months for BGB-3111-AU-003 and BGB-3111-206, respectively. Overall response rate (ORR) and complete response (CR) rate were 84.8% and 62.5%, and median duration of response, progression-free survival (PFS) and overall survival (OS) were 24.9, 25.8 and 38.2 months, respectively. After weighting, the PFS (median: NE vs. 21.1 months, P = 0.235) and OS (median: NE vs. 38.2 months, P = 0.057) were similar but numerically better in the second-line than later-line group. Zanubrutinib was well-tolerated with treatment discontinuation and dose reduction for adverse events in 12.5% and 2.7% of patients, respectively. Hypertension, major hemorrhage and atrial fibrillation/flutter rates were 11.6%, 5.4% and 1.8%, respectively. Zanubrutinib is efficacious in R/R MCL, with a favorable safety profile.
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http://dx.doi.org/10.1186/s13045-021-01174-3DOI Listing
October 2021

Genetic determinants of stress resistance in desiccated .

Appl Environ Microbiol 2021 Sep 29:AEM0168321. Epub 2021 Sep 29.

University of Alberta, Dept. of Agricultural, Food, and Nutritional Science, Edmonton, AB, Canada.

Enteric pathogens including are capable of long-term survival after desiccation, and resist heat treatment that are lethal to hydrated cells. The mechanisms of dry-heat resistance differ from wet heat resistance. To elucidate the mechanisms of dry-heat resistance in , screening of the dry-heat resistance of 108 strains representing 39 serotypes identified the 22 most resistant and the 8 most sensitive strains for comparative genome analysis. A total of 289 genes of the accessory genome were differently distributed between resistant and sensitive strains. Among these genes, 28 proteins with a putative relationship to stress resistance were selected for to quantify relative gene expression before and after desiccation, and expression by solid-state cultures on agar plates relative to cultures growing in liquid culture media. Of these 28 genes, 15 genes were upregulated (<0.05) after desiccation, or by solid-state cultures on agar plates. These 15 genes were cloned into the low-copy vector pRK767 under control of the promoter. The expression of 6 of these 15 genes of these genes increased (<0.05) resistance to dry-heat and to treatment with 500 MPa. Our finding extends the knowledge of mechanisms of stress resistance in desiccated to improve their control in dry food. This study directly targeted an increasing threat to food safety and developed knowledge and targeted strategies that can be used by the food industry to help reduce the risk of foodborne illness in their dry products and thereby reduce the overall burden of foodborne illness. Genomic and physiological analyses have elucidated mechanisms of bacterial resistance to many food preservation technologies including heat, pressure, disinfection chemicals, and UV light; however, information on bacterial mechanisms of resistance to dry-heat is scarce. Mechanisms of tolerance to desiccation likely also contribute to resistance to dry-heat but this assumption has not been verified experimentally. It remains unclear how mechanisms of resistance to wet heat relate to dry-heat resistance. This study will thus fill a knowledge gap to improve the safety of dry foods.
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http://dx.doi.org/10.1128/AEM.01683-21DOI Listing
September 2021

Estimating confidence intervals for cerebral autoregulation: a parametric bootstrap approach.

Physiol Meas 2021 Sep 17. Epub 2021 Sep 17.

Institute of Sound and Vibration Research, University of Southampton, University Road, Southampton, Select a county, SO171BJ, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND.

Cerebral autoregulation (CA) refers to the ability of the brain vasculature to control blood flow in the face of changing blood pressure. One of the methods commonly used to assess cerebral autoregulation, especially in participants at rest, is the analysis of phase derived from transfer function analysis (TFA),relating arterial blood pressure (ABP) to cerebral blood flow (CBF). This and other indexes of CA can provide consistent results when comparing groups of subjects (e.g. patients and healthy controls or normocapnia and hypercapnia) but can be quite variable within and between individuals. The objective of this paper is to present a novel parametric bootstrap method, used to estimate the sampling distribution and hence CIs of the mean phase estimate in the low frequency band, in order to optimise estimation of measures of CA function and allow more robust inferences on the status of CA from individual recordings. A set of simulations was used to verify the proposed method under controlled conditions. In 20 healthy adult volunteers (age 25.5 ± 3.5 years), ABP and CBF velocity (CBFV) were measured at rest, using a Finometer device and Transcranial Doppler (applied to the middle cerebral artery), respectively. For each volunteer, five individual recordings were taken on different days, each approximately 18 minutes long. Phase was estimated using TFA. Analysis of recorded data showed widely changing Confidence Intervals (CIs) over the duration of recordings, which could be reduced when noisy data and frequencies with low coherence were excluded from the analysis (Wilcoxon signed rank test p=0.0065). The TFA window-lengths of 50sgave smaller confidence intervals than lengths of 100s (p<0.001) or 20s (p<0.001), challenging the usual recommendation of 100s. The method adds a much needed flexible statistical tool for CA analysis in individual recordings.
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http://dx.doi.org/10.1088/1361-6579/ac27b8DOI Listing
September 2021

Ecology and Function of the Transmissible Locus of Stress Tolerance in Escherichia coli and Plant-Associated .

mSystems 2021 Aug 17;6(4):e0037821. Epub 2021 Aug 17.

University of Albertagrid.17089.37, Department of Agricultural, Food and Nutritional Science, Edmonton, Alberta, Canada.

The transmissible locus of stress tolerance (tLST) is a genomic island which confers resistance to heat and chlorine. In this study, we determined that the tLST is frequent in genomes of those that occur in association with plants as well as the intestines of humans and animals and are relevant as nosocomial pathogens, e.g., Klebsiella and species. The tLST is more frequent in environmental and clinical isolates of Klebsiella pneumoniae than in animal isolates, and heat and chlorine resistance of tLST-positive strains of K. pneumoniae matched the resistance of tLST-positive strains of Escherichia coli. The function of 13 tLST genes was determined by assessing the heat and chlorine resistance of E. coli MG1655 mutants. The deletion of , , , , , and reduced both heat and chlorine resistance; deletion of reduced only chlorine resistance. Genes coding for heat shock proteins , , and decreased the oxidation of cytoplasmic proteins, while decreased the oxidation of membrane lipids. The fitness cost of the tLST for E. coli MG1655 was assessed by pairwise competition experiments with isogenic tLST-positive or tLST-negative strains. The tLST imposes a fitness cost that is compensated for by frequent and lethal challenges with chlorine. All core genes need to be present to maintain the ecological advantage relative to the fitness cost. Taken together, core tLST genes are necessary to provide protection for E. coli against heat and chlorine stress, and the selective pressure for the tLST maintains core genes. The transmissible locus of stress tolerance (tLST) is a genomic island comprising 10 core genes that occurs in diverse and confers resistance to heat and chlorine. Experimentation described in the manuscript describes the physiological function of the core genes by characterization of the resistance of 13 single-knockout (KO) mutants and by characterization of protein and membrane oxidation in these strains after chlorine challenge. Results identify tLST resistance as a genomic island that is specific for those that occur in plant-associated habitats as well in the intestines of vertebrates. In addition, the ecological function of the genomic island was characterized by large-scale genomic analysis and competition experiments of wild-type and mutant strains. Results suggest that tLST-mediated resistance to chlorine may contribute to the persistence of nosocomial pathogens in hospitals.
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http://dx.doi.org/10.1128/mSystems.00378-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407380PMC
August 2021

Horizontal Transmission of Stress Resistance Genes Shape the Ecology of Beta- and Gamma-Proteobacteria.

Front Microbiol 2021 6;12:696522. Epub 2021 Jul 6.

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna, Sweden.

The transmissible locus of stress tolerance (tLST) is found mainly in beta- and gamma-Proteobacteria and confers tolerance to elevated temperature, pressure, and chlorine. This genomic island, previously referred to as transmissible locus of protein quality control or locus of heat resistance likely originates from an environmental bacterium thriving in extreme habitats, but has been widely transmitted by lateral gene transfer. Although highly conserved, the gene content on the island is subject to evolution and gene products such as small heat shock proteins are present in several functionally distinct sequence variants. A number of these genes are xenologs of core genome genes with the gene products to widen the substrate spectrum and to be highly (complementary) expressed thus their functionality to become dominant over core genome genes. In this review, we will present current knowledge of the function of core tLST genes and discuss current knowledge on selection and counter-selection processes that favor maintenance of the tLST island, with frequent acquisition of gene products involved in cyclic di-GMP signaling, in different habitats from the environment to animals and plants, processed animal and plant products, man-made environments, and subsequently humans.
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http://dx.doi.org/10.3389/fmicb.2021.696522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290217PMC
July 2021

The INfoMATAS project: Methods for assessing cerebral autoregulation in stroke.

J Cereb Blood Flow Metab 2021 Jul 19:271678X211029049. Epub 2021 Jul 19.

Department of Cardiovascular Sciences, Leicester Royal Infirmary, Leicester, UK.

Cerebral autoregulation refers to the physiological mechanism that aims to maintain blood flow to the brain approximately constant when blood pressure changes. Impairment of this protective mechanism has been linked to a number of serious clinical conditions, including carotid stenosis, head trauma, subarachnoid haemorrhage and stroke. While the concept and experimental evidence is well established, methods for the assessment of autoregulation in individual patients remains an open challenge, with no gold-standard having emerged. In the current review paper, we will outline some of the basic concepts of autoregulation, as a foundation for experimental protocols and signal analysis methods used to extract indexes of cerebral autoregulation. Measurement methods for blood flow and pressure are discussed, followed by an outline of signal pre-processing steps. An outline of the data analysis methods is then provided, linking the different approaches through their underlying principles and rationale. The methods cover correlation based approaches (e.g. Mx) through Transfer Function Analysis to non-linear, multivariate and time-variant approaches. Challenges in choosing which method may be 'best' and some directions for ongoing and future research conclude this work.
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http://dx.doi.org/10.1177/0271678X211029049DOI Listing
July 2021

A co-design of clinical virtual care pathways to engage and support families requiring neonatal intensive care in response to the COVID-19 pandemic (COVES study).

J Neonatal Nurs 2021 Jun 26. Epub 2021 Jun 26.

Parent Partner, Neonatal Intensive Care Unit, IWK Health, Halifax, Nova Scotia, Canada.

Background: In response to the COVID-19 pandemic, family presence restrictions in neonatal intensive care units (NICU) were enacted to limit disease transmission. This has resulted in communication challenges, negatively impacting family integrated care.

Aim: To develop clinical care pathways to ensure optimal neonatal care to support families in response to parental presence restrictions imposed during the COVID-19 pandemic.

Methods: An agile, co-design process utilizing expert consensus of a large interdisciplinary team and focus groups and semi-structured interviews with families and HCPs were used to co-design clinical virtual care pathways.

Results: Three clinical virtual care pathways were co-designed: (1) building and maintaining relationships between family and healthcare providers; (2) awareness of resources; and (3) standardized COVID-19 messaging. Modifications were made to optimize uptake and utilization in the clinical areas.

Conclusion: Clinical care virtual pathways were successfully co-designed to meet these needs to ensure more equitable family centered care.
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http://dx.doi.org/10.1016/j.jnn.2021.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233852PMC
June 2021

Zanubrutinib for the treatment of relapsed or refractory mantle cell lymphoma.

Blood Adv 2021 06;5(12):2577-2585

Concord Repatriation Hospital, The University of Sydney, Sydney, NSW, Australia.

Zanubrutinib, a highly selective Bruton tyrosine kinase inhibitor, was evaluated in a phase 1/2 study in patients with various B-cell malignancies. In the subgroup of patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL), zanubrutinib was administered as 160 mg twice daily (n = 14), 320 mg once daily (n = 18), or ≤160 mg total dose (n = 5). Herein, we report results for patients receiving a total daily dose of 320 mg (N = 32). Median study follow-up was 18.8 months. Eighteen patients discontinued treatment, 10 because of progressive disease and 8 because of adverse events (AEs); 1 AE (peripheral edema) was considered to be related to zanubrutinib treatment. The most common AEs were diarrhea (43.8%), contusion (37.5%), constipation (31.3%), and upper respiratory tract infection (31.3%). Infection was the most commonly reported AE of interest (18.8% of patients experienced grade ≥3 infection). At least 1 AE of grade ≥3 was reported in 59.4% of patients; grade ≥3 AEs that were reported in >2 patients were anemia (12.5%), pneumonia (9.4%), and myalgia (9.4%). Overall response rate was 84%, with 25% achieving a complete response. Median duration of response was 18.5 months. Median progression-free survival (PFS) was 21.1 months. Zanubrutinib was well tolerated and demonstrated activity in patients with R/R MCL. The trial is registered at www.clinicaltrials.gov as #NCT02343120.
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http://dx.doi.org/10.1182/bloodadvances.2020004074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270663PMC
June 2021

Adapting stepped care: Changes to service delivery format in the context of high demand.

Psychol Serv 2021 Jun 10. Epub 2021 Jun 10.

Counseling and Psychological Services, Brigham Young University.

Given the ongoing dilemma for college counseling centers to meet steady increases in demand for services, this study outlines the implementation of an adapted stepped care model in a university counseling center. Our adapted model focused, as do other stepped care models, on treatment planning and lower-intensity interventions, with the addition of the intensive therapy option being provided on a weekly basis. We adopted our stepped care model across a large center and hypothesized that after implementation we would be able to serve a similar number of clients as our previous model and that treatment outcomes for these clients would improve. Descriptive data and regression analyses demonstrated support for our hypotheses, including an increased likelihood of clinically significant improvement for clients postimplementation. Implications for adapting service delivery models using practice-based evidence are discussed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/ser0000564DOI Listing
June 2021

Subgroup analysis of ICARIA-MM study in relapsed/refractory multiple myeloma patients with high-risk cytogenetics.

Br J Haematol 2021 Jul 25;194(1):120-131. Epub 2021 May 25.

Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Treatment benefit in multiple myeloma (MM) patients with high-risk cytogenetics remains suboptimal. The phase 3 ICARIA-MM trial (NCT02990338) showed that isatuximab plus pomalidomide-dexamethasone prolongs median progression-free survival (mPFS) in patients with relapsed/refractory MM (RRMM). This subgroup analysis of ICARIA-MM compared the benefit of isatuximab in high-risk [defined by the presence of del(17p), t(4;14) or t(14;16)] versus standard-risk patients. The efficacy of isatuximab in patients with gain(1q21) abnormality was also assessed in a retrospective subgroup analysis. In ICARIA-MM, 307 patients received isatuximab-pomalidomide-dexamethasone (n = 154) or pomalidomide-dexamethasone (n = 153). Isatuximab (10 mg/kg intravenously) was given weekly in the first 28-day cycle, and every other week thereafter. Standard pomalidomide-dexamethasone doses were given. Isatuximab-pomalidomide-dexamethasone improved mPFS (7·5 vs 3·7 months; HR, 0·66; 95% CI, 0·33-1·28) and overall response rate (ORR, 50·0% vs 16·7%) in high-risk patients. In patients with isolated gain(1q21), isatuximab addition improved mPFS (11·2 vs 4·6 months; HR, 0·50; 95% CI, 0·28-0·88) and ORR (53·6% vs 27·6%). More grade ≥3 adverse events occurred in high-risk patients receiving isatuximab (95·7%) versus the control group (67·6%); however, isatuximab did not increase events leading to discontinuation or treatment-related mortality. Isatuximab-pomalidomide-dexamethasone provides a consistent benefit over pomalidomide-dexamethasone treatment in RRMM patients regardless of cytogenetic risk.
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http://dx.doi.org/10.1111/bjh.17499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361732PMC
July 2021

Variant Median Nerve Anatomy: Ultrasound Evidence of a Pseudoconduction Block.

J Clin Neuromuscul Dis 2021 Jun;22(4):209-213

Department of Neurology, Division of Neuromuscular Diseases and Clinical Neurophysiology Laboratories, Icahn School of Medicine, New York, NY.

Introduction: A conduction block at a noncompressible site warrants further investigation.

Methods And Materials: A 36-year-old woman with a history of Hodgkin lymphoma and chemotherapy-induced polyneuropathy developed bilateral hand numbness and paresthesias. Workup revealed bilateral carpal tunnel syndrome and an apparent superimposed conduction block of the median nerve in the forearm. Given the history of cancer, there was concern for an infiltrative or an immune-mediated process.

Results: Neuromuscular ultrasound demonstrated that the median nerve descended the upper extremity along an atypical path, deep along the posteromedial aspect of the upper arm, and relatively medially in the forearm. Ultrasound-directed nerve stimulation revealed there was no conduction block. This anatomical variant has been rarely described and has not been reported previously to mimic conduction block or been documented via ultrasound.

Conclusions: This case demonstrates that neuromuscular ultrasound may supplement the electrodiagnostic study and limit confounding technical factors because of rare anatomic variation.
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http://dx.doi.org/10.1097/CND.0000000000000325DOI Listing
June 2021

Preferential coupling of diamond NV centres in step-index fibres.

Opt Express 2021 May;29(10):14425-14437

Diamonds containing the negatively charged nitrogen-vacancy centre are a promising system for room-temperature magnetometry. The combination of nano- and micro-diamond particles with optical fibres provides an option for deploying nitrogen-vacancy magnetometers in harsh and challenging environments. Here we numerically explore the coupling efficiency from nitrogen-vacancy centres within a diamond doped at the core/clad interface across a range of commercially available fibre types so as to inform the design process for a diamond in fibre magnetometers. We determine coupling efficiencies from nitrogen-vacancy centres to the guided modes of a step-index fibre and predict the optically detected magnetic resonance (ODMR) generated by a ensemble of four nitrogen-vacancy centres in this hybrid fibre system. Our results show that the coupling efficiency is enhanced with a high refractive index difference between the fibre core and cladding and depends on the radial position of the nitrogen-vacancy centres in the fibre core. Our ODMR simulations show that due to the preferential coupling of the nitrogen-vacancy emission to the fibre guided modes, certain magnetometry features such as ODMR contrast can be enhanced and lead to improved sensitivity in such diamond-fibre systems, relative to conventional diamond only ensemble geometries.
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http://dx.doi.org/10.1364/OE.417825DOI Listing
May 2021

Caregiver Presence and Involvement in a Canadian Neonatal Intensive Care Unit: An Observational Cohort Study.

J Pediatr Nurs 2021 Sep-Oct;60:123-129. Epub 2021 May 1.

IWK Health Centre, Nova Scotia, Canada.

Background: Presence in the neonatal intensive care unit (NICU) is a vital step for caregivers initiating involvement, such as skin-to-skin contact, holding or singing/reading to their newborn. Little is known about caregiver presence and involvement in Canadian NICU's context by caregiver type (mother, father, other), and the association between maternal presence and key maternal and newborn characteristics.

Purpose: The primary objective was to examine the presence and involvement of family caregivers in the NICU. The secondary objective was to examine the relationship between maternal presence and maternal and newborn characteristics.

Design And Methods: A prospective observational cohort study in an open bay setting of an Eastern Canadian NICU. Presence (physically present at the newborn's bedside) and involvement (e.g., skin-to-skin, singing/reading) were tracked daily by families in the NICU until discharge. Demographic information was also collected.

Results: Participants included 142 mothers and their newborns. Mothers were present 8.7 h/day, fathers were present 4.1 h/day, and other caregivers were present 1.8 h/day in the NICU in the first 34 days. Mothers were involved in care activities 50% of the time they were present in the NICU, whereas fathers and other caregivers were spending 20% and 6% of their time respectively. Regression identified maternal age, distance to home, parity, birthweight, and length of stay to be statistically significant variables related to maternal presence.

Conclusions: There is variation in presence and involvement by caregiver type. Targeted interventions to maintain and increase mothers, fathers and other caregivers' presence and involvement in care throughout their stay in the NICU are recommended.
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http://dx.doi.org/10.1016/j.pedn.2021.04.023DOI Listing
October 2021

Management of Neuropathic Pain in the Geriatric Population.

Clin Geriatr Med 2021 05;37(2):361-376

Department of Neurology Division of Neuromuscular Diseases and Clinical Neurophysiology Laboratories, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, Annenberg, 2nd Floor, Box 1052, New York, NY 10029, USA.

Neuropathic pain is common in the geriatric population. Diagnosis requires a thorough history and physical examination to differentiate it from other types of pain. Once diagnosed, further workup is required to elucidate the cause, including potential reversible causes of neuropathy. When treating neuropathic pain in the elderly, it is important to consider patients' comorbidities and other medications to avoid drug-drug interactions and iatrogenic effects given the physiologic changes of drug metabolism in the elderly. Nonsystemic therapies and topical medications should be considered. Systemic medications should be started at low dose and titrated up slowly with frequent monitoring for adverse effects.
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http://dx.doi.org/10.1016/j.cger.2021.01.008DOI Listing
May 2021

Contribution of the Locus of Heat Resistance to Growth and Survival of at Alkaline pH and at Alkaline pH in the Presence of Chlorine.

Microorganisms 2021 Mar 28;9(4). Epub 2021 Mar 28.

Department of Agricultural, Food and Nutritional Science, 4-10 Ag/For Centre, University of Alberta, Edmonton, AB T6G 2P5, Canada.

The locus of heat resistance (LHR) confers resistance to extreme heat, chlorine and oxidative stress in . This study aimed to determine the function of the LHR in maintaining bacterial cell envelope homeostasis, the regulation of the genes comprising the LHR and the contribution of the LHR to alkaline pH response. The presence of the LHR did not affect the activity of the Cpx two-component regulatory system in , which was measured to quantify cell envelope stress. The LHR did not alter MG1655 growth rate in the range of pH 6.9 to 9.2. However, RT-qPCR results indicated that the expression of the LHR was elevated at pH 8.0 when CpxR was absent. The LHR did not improve survival of MG1655 at extreme alkaline pH (pH = 11.0 to 11.2) but improved survival at pH 11.0 in the presence of chlorine. Therefore, we conclude that the LHR confers resistance to extreme alkaline pH in the presence of oxidizing agents. Resistance to alkaline pH is regulated by an endogenous mechanism, including the Cpx envelope stress response, whereas the LHR confers resistance to extreme alkaline pH only in the presence of additional stress such as chlorine.
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http://dx.doi.org/10.3390/microorganisms9040701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067161PMC
March 2021

Multichannel search strategy for improving the detection of auditory steady-state response.

Med Biol Eng Comput 2021 Feb 25;59(2):391-399. Epub 2021 Jan 25.

Department of Electrical Engineering, Federal University of Viçosa, Viçosa, MG, Brazil.

Auditory steady-state response (ASSR) is useful for hearing threshold estimation. The ASSR is usually detected with objective response detectors (ORD). The performance of these detectors depends on the signal-to-noise ratio (SNR) as well as the signal length. Since it is undesirable to increase the signal length, then, this work provides a multivariate technique for improving the SNR and consequently the detection power. We propose the insertion of a short calibration step before the detection protocol, in order to perform a search among the available electroencephalogram (EEG) derivations and select the derivation with the highest SNR. The ORD used in this work was the magnitude-squared coherence (MSC). The standard detection protocol is to use the same EEG derivation in all exams. Using 22-scalp positions, the new technique achieved a detection rate higher than that obtained in 99.13% of the standard detection protocol. When restrictions were applied to the search, a superior performance was achieved. Thus, the technique proposed was able to track the best EEG derivations before exams and seems to be able to deal with the variability between individuals and between sessions.
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http://dx.doi.org/10.1007/s11517-021-02323-zDOI Listing
February 2021

A critical review of the capsaicin 8% patch for the treatment of neuropathic pain associated with diabetic peripheral neuropathy of the feet in adults.

Expert Rev Neurother 2021 Mar 4;21(3):259-266. Epub 2021 Feb 4.

Neurology, Mount Sinai School of Medicine, 1468 Madison Avenue, New York, NY 10019.

Introduction: Diabetes is an increasingly prevalent disorder affecting nearly 1-in-5 adults, of which half will experience diabetic peripheral neuropathy (DPN) and a quarter will suffer from diabetic peripheral nerve pain (DPNP), severely impacting quality of life. The currently approved treatment options are typically centrally acting agents whose use is limited by systemic effects and drug interactions. The capsaicin 8% dermal patch was recently approved by the U.S. FDA for the treatment of DPNP.

Areas Covered: The authors review the available literature regarding the use of high-concentration capsaicin 8% patch for the treatment of diabetic peripheral neuropathy and neuropathic pain and discuss implementing its use in clinical practice.

Expert Opinion: The high-concentration capsaicin 8% patch is an effective and well-tolerated treatment option for treating DPNP. Capsaicin 8% patch may be used alone or in combination with other oral therapies and can provide rapid and sustained neuropathic pain relief following a single application and is safe and effective when used long term.
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http://dx.doi.org/10.1080/14737175.2021.1874920DOI Listing
March 2021

Tolerability and Efficacy of Customized IncobotulinumtoxinA Injections for Essential Tremor: A Randomized, Double-Blind, Placebo-Controlled Study.

Toxins (Basel) 2020 Dec 20;12(12). Epub 2020 Dec 20.

Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

In this first, double-blind, randomized, placebo-controlled exploratory trial, we evaluate the efficacy and safety of incobotulinumtoxinA and feasibility of using kinematic tremor assessment to aid in the planning of muscle selection in a multicenter setting. Reproducibility of the planning technology to other clinical sites was explored. In this trial (NCT02207946), patients with upper-limb essential tremor (ET) were randomized 2:1 to a single treatment cycle of incobotulinumtoxinA or placebo. A tremor kinematic analytics investigational device was used to define a customized muscle set for injection, related to the pattern of the wrist, forearm, elbow, and shoulder tremor for each patient, and the incobotulinumtoxinA dose per muscle (total ≤ 200 U). Fahn-Tolosa-Marin (FTM) Part B motor performance score, Global Impression of Change Scale (GICS), and kinematic analysis-based efficacy evaluations were assessed. Thirty patients were randomized (incobotulinumtoxinA, = 19; placebo, = 11). FTM motor performance scores showed greater improvement with incobotulinumtoxinA versus placebo at Week 4 ( 0.003) and Week 8 ( 0.031). The physician-rated GICS score indicated improvement with incobotulinumtoxinA versus placebo at Week 4 ( < 0.05). IncobotulinumtoxinA also decreased accelerometric hand-tremor amplitude versus placebo from baseline to Week 4 ( 0.004) and Week 8 ( < 0.001), with persistent tremor reduction up to 24 weeks post-injection. IncobotulinumtoxinA produced a slight and transient reduction of maximal grip strength versus placebo; two patients reported localized finger muscle weakness. Customized incobotulinumtoxinA injections decreased tremor severity and improved hand motor function in patients with upper-limb ET after a single injection cycle, with a favorable tolerability profile. The study showed that tremor kinematic analytics technology could be successfully scaled for use in other clinical sites.
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http://dx.doi.org/10.3390/toxins12120807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766785PMC
December 2020

What are they doing? A national survey of help-seeking and relationship-repair behavior of individuals who are thinking about divorce.

J Marital Fam Ther 2021 Jan 6. Epub 2021 Jan 6.

School of Family Life, Brigham Young University, Provo, UT, USA.

Guided by the Stages of Change (SOC) model, we explored relationship-repair behaviors among those thinking about divorce, employing a recent national longitudinal survey of married individuals (N = 745). Person-centered analyses explored whether there were distinct typologies of relationship-repair behaviors. We found four distinct classes: Intense Seekers (6%), who engaged at high levels of all kinds of repair behaviors, including professional services; Moderate-fading Seekers (14%), who engaged in moderate levels of various repair behaviors, including professional services, but did not sustain that behavior over a year; and Minimal-private Seekers (42%) and Private-sustained Seekers (38%), who eschewed professional services and engaged in low-to-moderate personal and private repair behaviors. We discuss possible applications of the SOC model to the divorce decision-making process and conclude with implications for practice, including the need to allocate greater attention to personal and self-help interventions that match the way most people try to repair their relationships.
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http://dx.doi.org/10.1111/jmft.12480DOI Listing
January 2021

Comparative Genomics and In Vitro Plant Growth Promotion and Biocontrol Traits of Lactic Acid Bacteria from the Wheat Rhizosphere.

Microorganisms 2020 Dec 30;9(1). Epub 2020 Dec 30.

Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a, 70126 Bari, Italy.

This study aimed to isolate lactic acid bacteria (LAB) from wheat rhizosphere, to characterize their in vitro plant growth promoting activities and to differentiate plant-associated LAB from those associated with foods or human disease through comparative genomic analysis. subsp. and were isolated using de Man-Rogosa-Sharpe (MRS) and Glucose Yeast Peptone (GYP) as enrichment culture media. Comparative genomic analyses showed that plant-associated LAB strains were enriched in genes coding for bacteriocin production when compared to strains from other ecosystems. Isolates of and did not produce physiologically relevant concentrations of the phyto-hormone indolacetic acid. All isolates solubilized high amount of phosphate and 12 of 16 strains solubilized potassium. LB5, LB6, LB7, and LB9 inhibited the plant pathogenic to the same extent as two strains of sp. However, the antifungal activity of the abovementioned LAB strains depended on the medium of cultivation and a low pH while antifungal activity of spp. was independent of the growth medium and likely relates to antifungal lipopeptides. This study showed the potential of rhizospheric LAB for future application as biofertilizers in agriculture.
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http://dx.doi.org/10.3390/microorganisms9010078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823429PMC
December 2020

Single-cell transcriptomic profiling provides insights into retinal endothelial barrier properties.

Mol Vis 2020 27;26:766-779. Epub 2020 Nov 27.

Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland.

Purpose: To better characterize retinal endothelial barrier properties through analysis of individual transcriptomes of primary bovine retinal microvascular endothelial cells (RMECs).

Methods: Individual RMECs were captured on the Fluidigm C1 system, cDNA libraries were prepared using a Nextera XT kit, and sequencing was performed on a NextSeq system (Illumina). Data analysis was performed using R packages Scater, SC3, and Seurat, and the browser application Automated Single-cell Analysis Pipeline (ASAP). Alternative splicing events in single cells were quantified with Outrigger. Cytoscape was used for network analyses.

Results: Application of a single-cell RNA sequencing (scRNA-seq) analysis workflow showed that RMECs form a relatively homogeneous population in culture, with the main differences related to proliferation status. Expression of markers from along the arteriovenous tree suggested that most cells originated from capillaries. Average gene expression levels across all cells were used to develop an in silico model of the inner blood-retina barrier incorporating junctional proteins not previously reported within the retinal vasculature. Correlation of barrier gene expression among individual cells revealed a subgroup of genes highly correlated with PECAM-1 at the center of the correlation network. Numerous alternative splicing events involving exons within microvascular barrier genes were observed, and in many cases, individual cells expressed one isoform exclusively.

Conclusions: We optimized a workflow for single-cell transcriptomics in primary RMECs. The results provide fundamental insights into the genes involved in formation of the retinal-microvascular barrier.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765706PMC
August 2021

Systematic Comparison of Vesicular Targeting Signals Leads to the Development of Genetically Encoded Vesicular Fluorescent Zn and pH Sensors.

ACS Sens 2020 12 11;5(12):3879-3891. Epub 2020 Dec 11.

Department of Biochemistry and BioFrontiers Institute, University of Colorado Boulder, 3415 Colorado Ave, UCB 596, Boulder, Colorado 80309-0401, United States.

Genetically encoded fluorescent sensors have been widely used to illuminate secretory vesicle dynamics and the vesicular lumen, including Zn and pH, in living cells. However, vesicular sensors have a tendency to mislocalize and are susceptible to the acidic intraluminal pH. In this study, we performed a systematic comparison of five different vesicular proteins to target the fluorescent protein mCherry and a Zn Förster resonance energy transfer (FRET) sensor to secretory vesicles. We found that motifs derived from vesicular cargo proteins, including chromogranin A (CgA), target vesicular puncta with greater efficacy than transmembrane proteins. To characterize vesicular Zn levels, we developed CgA-Zn FRET sensor fusions with existing sensors ZapCY1 and eCALWY-4 and characterized subcellular localization and the influence of pH on sensor performance. We simultaneously monitored Zn and pH in individual secretory vesicles by leveraging the acceptor fluorescent protein as a pH sensor and found that pH influenced FRET measurements . While unable to characterize vesicular Zn at the single-vesicle level, we were able to monitor Zn dynamics in populations of vesicles and detected high vesicular Zn in MIN6 cells compared to lower levels in the prostate cancer cell line LnCaP. The combination of CgA-ZapCY1 and CgA-eCALWY-4 allows for measurement of Zn from pM to nM ranges.
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http://dx.doi.org/10.1021/acssensors.0c01231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444068PMC
December 2020

Corteva Agriscience's perspective and commitment to managing herbicide resistance.

Pest Manag Sci 2021 Apr 19;77(4):1572-1577. Epub 2020 Dec 19.

Corteva Agriscience, Indianapolis, IN, USA.

Chemical weed control has been widely adopted and has led to increased efficiency and reduced crop production costs. With the increased use of herbicides and the introduction of herbicide-tolerant crops we have also seen an increase in herbicide resistant weeds which presents a challenge for farmers and land managers. It is incumbent upon the agriculture industry to be an indispensable partner in leading policy, research, education, and best management practices related to herbicide resistance. Corteva Agriscience is an active, engaged partner in herbicide resistance research, education, and communication globally to enable the long-term sustainable use of herbicide-tolerant crop traits and herbicides. Some of the key components of our commitment are highlighted in this Perspective paper and include memberships, partnerships, close involvement with CropLife International (and regional CropLife organizations), and Herbicide Resistance Action Committees at the Global, regional and country level, technical leadership and engagement in multiple scientific societies, and collaboration with universities and research institutes. Corteva is committed to advancing sustainable agriculture to enrich lives and our planet for generations to come and this drives our action through the entire product lifecycle and with our customers and consumers.
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http://dx.doi.org/10.1002/ps.6214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986632PMC
April 2021

Efficient Detection of Cortical Auditory Evoked Potentials in Adults Using Bootstrapped Methods.

Ear Hear 2020 11 30;42(3):574-583. Epub 2020 Nov 30.

Institute of Sound and Vibration Research, Faculty of Engineering and the Environment, University of Southampton, United Kingdom.

Background: Statistical detection methods are useful tools for assisting clinicians with cortical auditory evoked potential (CAEP) detection, and can help improve the overall efficiency and reliability of the test. However, many of these detection methods rely on parametric distributions when evaluating test significance, and thus make various assumptions regarding the electroencephalogram (EEG) data. When these assumptions are violated, reduced test sensitivities and/or increased or decreased false-positive rates can be expected. As an alternative to the parametric approach, test significance can be evaluated using a bootstrap, which does not require some of the aforementioned assumptions. Bootstrapping also permits a large amount of freedom when choosing or designing the statistical test for response detection, as the distributions underlying the test statistic no longer need to be known prior to the test.

Objectives: To improve the reliability and efficiency of CAEP-related applications by improving the specificity and sensitivity of objective CAEP detection methods.

Design: The methods included in the assessment were Hotelling's T2 test, the Fmp, four modified q-sample statistics, and various template-based detection methods (calculated between the ensemble coherent average and some predefined template), including the correlation coefficient, covariance, and dynamic time-warping (DTW). The assessment was carried out using both simulations and a CAEP threshold series collected from 23 adults with normal hearing.

Results: The most sensitive method was DTW, evaluated using the bootstrap, with maximum increases in test sensitivity (relative to the conventional Hotelling's T2 test) of up to 30%. An important factor underlying the performance of DTW is that the template adopted for the analysis correlates well with the subjects' CAEP.

Conclusion: When subjects' CAEP morphology is approximately known before the test, then the DTW algorithm provides a highly sensitive method for CAEP detection.
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http://dx.doi.org/10.1097/AUD.0000000000000959DOI Listing
November 2020

Microbial fuel cell biosensor for the determination of biochemical oxygen demand of wastewater samples containing readily and slowly biodegradable organics.

Biotechnol Lett 2021 Feb 27;43(2):445-454. Epub 2020 Nov 27.

Okinawa Institute of Science and Technology, 1919-1 Tancha, Onna-Son, Kunigami-gun, Okinawa, 904-0495, Japan.

Objectives: Single-chamber air cathode microbial fuel cells (MFCs) were applied as biosensors for biochemical oxygen demand (BOD) measurement of real wastewaters with considerable suspended and/or slowly biodegradable organic content.

Results: The measurement method consists of batch sample injection, continuous measurement of cell voltage and calculation of total charge (Q) gained during the biodegradation of organic content. Diverse samples were analyzed: acetate and peptone samples containing only soluble readily biodegradable substrates; corn starch and milk samples with suspended and colloidal organics; real domestic and brewery wastewaters. Linear regression fitted to the Q vs. BOD measurement points of the real wastewaters provided high (> 0.985) R values. Time requirement of the measurement varied from 1 to 4 days, depending on the composition of the sample.

Conclusions: Relative error of BOD measured in the MFCs comparing with BOD was less than 10%, thus the method might be a good basis for the development of on-site automatic BOD sensors for real wastewater samples.
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http://dx.doi.org/10.1007/s10529-020-03050-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822768PMC
February 2021

Re-examining ferritin-bound iron: current and developing clinical tools.

Clin Chem Lab Med 2021 02 22;59(3):459-471. Epub 2020 Oct 22.

School of Physics, University of Melbourne, Parkville, VIC, Australia.

Iron is a highly important metal ion cofactor within the human body, necessary for haemoglobin synthesis, and required by a wide range of enzymes for essential metabolic processes. Iron deficiency and overload both pose significant health concerns and are relatively common world-wide health hazards. Effective measurement of total iron stores is a primary tool for both identifying abnormal iron levels and tracking changes in clinical settings. Population based data is also essential for tracking nutritional trends. This review article provides an overview of the strengths and limitations associated with current techniques for diagnosing iron status, which sets a basis to discuss the potential of a new serum marker - ferritin-bound iron - and the improvement it could offer to iron assessment.
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http://dx.doi.org/10.1515/cclm-2020-1095DOI Listing
February 2021

Zanubrutinib monotherapy for patients with treatment naïve chronic lymphocytic leukemia and 17p deletion.

Haematologica 2020 10 13;106(9):2354-2363. Epub 2020 Oct 13.

Dana-Farber Cancer Institute, Boston, MA.

Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naïve patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase 3 SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42 - 86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0 - 26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI, 79.0 - 94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI, 88.4 - 98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade ≥ 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered at ClinicalTrials.gov as #NCT03336333.
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http://dx.doi.org/10.3324/haematol.2020.259432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409041PMC
October 2020

Electrospun Nanodiamond-Silk Fibroin Membranes: A Multifunctional Platform for Biosensing and Wound-Healing Applications.

ACS Appl Mater Interfaces 2020 Oct 13;12(43):48408-48419. Epub 2020 Oct 13.

School of Science, RMIT University, Melbourne, Victoria 3001, Australia.

Next generation wound care technology capable of diagnosing wound parameters, promoting healthy cell growth, and reducing pathogenic infections noninvasively would provide patients with an improved standard of care and accelerated wound repair. Temperature is one of the indicating biomarkers specific to chronic wounds. This work reports a hybrid, multifunctional optical material platform-nanodiamond (ND)-silk membranes as biopolymer dressings capable of temperature sensing and promoting wound healing. The hybrid structure was fabricated through electrospinning, and 3D submicron fibrous membranes with high porosity were formed. Silk fibers are capable of compensating for the lack of an extracellular matrix at the wound site, supporting the wound-healing process. Negatively charged nitrogen vacancy (NV) color centers in NDs exhibit optically detected magnetic resonance (ODMR) and act as nanoscale thermometers. This can be exploited to sense temperature variations associated with the presence of infection or inflammation in a wound, without physically removing the dressing. Our results show that the presence of NDs in the hybrid ND-silk membranes improves the thermal stability of silk fibers. NV color centers in NDs embedded in silk fibers exhibit well-retained fluorescence and ODMR. Using the NV centers as fluorescent nanoscale thermometers, we achieved temperature sensing in 25-50 °C, including the biologically relevant temperature window, for cell-grown ND-silk membranes. An enhancement (∼1.5× on average) in the temperature sensitivity of the NV centers was observed for the hybrid materials. The hybrid membranes were further tested in a murine wound-healing model and demonstrated biocompatibility and equivalent wound closure rates as the control wounds. Additionally, the hybrid ND-silk membranes exhibited selective antifouling and biocidal propensity toward Gram-negative and , while no effect was observed on Gram-positive .
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http://dx.doi.org/10.1021/acsami.0c15612DOI Listing
October 2020

A Multi-Omics Approach Identifies Key Regulatory Pathways Induced by Long-Term Zinc Supplementation in Human Primary Retinal Pigment Epithelium.

Nutrients 2020 Oct 6;12(10). Epub 2020 Oct 6.

Wellcome Wolfson Institute for Experimental Medicine, Queen's University of Belfast, Belfast BT97BL, Northern Ireland, UK.

In age-related macular degeneration (AMD), both systemic and local zinc levels decline. Elevation of zinc in clinical studies delayed the progression to end-stage AMD. However, the molecular pathways underpinning this beneficial effect are not yet identified. In this study, we used differentiated primary human fetal retinal pigment epithelium (RPE) cultures and long-term zinc supplementation to carry out a combined transcriptome, proteome and secretome analysis from three genetically different human donors. After combining significant differences, we identified the complex molecular networks using Database for Annotation, Visualization and Integrated Discovery (DAVID) and Ingenuity Pathway Analysis (IPA). The cell cultures from the three donors showed extensive pigmentation, development of microvilli and basal infoldings and responded to zinc supplementation with an increase in transepithelial electrical resistance (TEER) (apical supplementation: 443.2 ± 79.3%, basal supplementation: 424.9 ± 116.8%, compared to control: 317.5 ± 98.2%). Significant changes were observed in the expression of 1044 genes, 151 cellular proteins and 124 secreted proteins. Gene set enrichment analysis revealed changes in specific molecular pathways related to cell adhesion/polarity, extracellular matrix organization, protein processing/transport, and oxidative stress response by zinc and identified a key upstream regulator effect similar to that of TGFB1.
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http://dx.doi.org/10.3390/nu12103051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601425PMC
October 2020
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