Publications by authors named "Mark Baker"

499 Publications

Noninvasive vagus nerve stimulation in Parkinson's disease: current status and future prospects.

Expert Rev Med Devices 2021 Sep 8:1-14. Epub 2021 Sep 8.

Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.

Introduction: Parkinson's disease (PD) is a common progressive neurodegenerative disorder with multifactorial etiology. While dopaminergic medication is the standard therapy in PD, it provides limited symptomatic treatment and non-pharmacological interventions are currently being trialed.

Areas Covered: Recent pathophysiological theories of Parkinson's suggest that aggregated α-synuclein form in the gut and spread to nuclei in the brainstem via autonomic connections. In this paper, we review the novel hypothesis that noninvasive vagus nerve stimulation (nVNS), targeting efferent and afferent vagal projections, is a promising therapeutic tool to improve gait and cognitive control and ameliorate non-motor symptoms in people with Parkinson's. We conducted an unstructured search of the literature for any studies employing nVNS in PD as well as for studies examining the efficacy of nVNS on improving cognitive function and where nVNS has been applied to co-occurring conditions in PD.

Expert Opinion: Evidence of nVNS as a novel therapeutic to improve gait in PD is preliminary, but early signs indicate the possibility that nVNS may be useful to target dopa-resistant gait characteristics in early PD. The evidence for nVNS as a therapeutic tool is, however, limited and further studies are needed in both brain health and disease.
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http://dx.doi.org/10.1080/17434440.2021.1969913DOI Listing
September 2021

Core Histones Are Constituents of the Perinuclear Theca of Murid Spermatozoa: An Assessment of Their Synthesis and Assembly during Spermiogenesis and Function after Gametic Fusion.

Int J Mol Sci 2021 Jul 29;22(15). Epub 2021 Jul 29.

Department of Biomedical and Molecular Sciences, Queen's University, Botterell Hall, 18 Stuart Street, Kingston, ON K7L 3N6, Canada.

The perinuclear theca (PT) of the eutherian sperm head is a cytoskeletal-like structure that houses proteins involved in important cellular processes during spermiogenesis and fertilization. Building upon our novel discovery of non-nuclear histones in the bovine PT, we sought to investigate whether this PT localization was a conserved feature of eutherian sperm. Employing cell fractionation, immunodetection, mass spectrometry, qPCR, and intracytoplasmic sperm injections (ICSI), we examined the localization, developmental origin, and functional potential of histones from the murid PT. Immunodetection localized histones to the post-acrosomal sheath (PAS) and the perforatorium (PERF) of the PT but showed an absence in the sperm nucleus. MS/MS analysis of selectively extracted PT histones indicated that predominately core histones (i.e., H3, H3.3, H2B, H2A, H2AX, and H4) populate the murid PT. These core histones appear to be -synthesized in round spermatids and assembled via the manchette during spermatid elongation. Mouse ICSI results suggest that early embryonic development is delayed in the absence of PT-derived core histones. Here, we provide evidence that core histones are -synthesized prior to PT assembly and deposited in PT sub-compartments for subsequent involvement in chromatin remodeling of the male pronucleus post-fertilization.
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http://dx.doi.org/10.3390/ijms22158119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347300PMC
July 2021

Comparing Stop Signal Reaction Times in Alzheimer's and Parkinson's Disease.

Can J Neurol Sci 2021 Jul 29:1-10. Epub 2021 Jul 29.

Department of Neurology, RGCM Research Centre, Institute of Neurosciences, Kolkata, India.

Background: To investigate the relative contributions of cerebral cortex and basal ganglia to movement stopping, we tested the optimum combination Stop Signal Reaction Time (ocSSRT) and median visual reaction time (RT) in patients with Alzheimer's disease (AD) and Parkinson's disease (PD) and compared values with data from healthy controls.

Methods: Thirty-five PD patients, 22 AD patients, and 29 healthy controls were recruited to this study. RT and ocSSRT were measured using a hand-held battery-operated electronic box through a stop signal paradigm.

Result: The mean ocSSRT was found to be 309 ms, 368 ms, and 265 ms in AD, PD, and healthy controls, respectively, and significantly prolonged in PD compared to healthy controls (p = 0.001). The ocSSRT but not RT could separate AD from PD patients (p = 0.022).

Conclusion: Our data suggest that subcortical networks encompassing dopaminergic pathways in the basal ganglia play a more important role than cortical networks in movement-stopping. Combining ocSSRT with other putative indices or biomarkers of AD (and other dementias) could increase the accuracy of early diagnosis.
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http://dx.doi.org/10.1017/cjn.2021.184DOI Listing
July 2021

Neurological manifestations of SARS-CoV-2 infection in hospitalised children and adolescents in the UK: a prospective national cohort study.

Lancet Child Adolesc Health 2021 09 15;5(9):631-641. Epub 2021 Jul 15.

Alder Hey Children's NHS Foundation Trust, Liverpool, UK.

Background: The spectrum of neurological and psychiatric complications associated with paediatric SARS-CoV-2 infection is poorly understood. We aimed to analyse the range and prevalence of these complications in hospitalised children and adolescents.

Methods: We did a prospective national cohort study in the UK using an online network of secure rapid-response notification portals established by the CoroNerve study group. Paediatric neurologists were invited to notify any children and adolescents (age <18 years) admitted to hospital with neurological or psychiatric disorders in whom they considered SARS-CoV-2 infection to be relevant to the presentation. Patients were excluded if they did not have a neurological consultation or neurological investigations or both, or did not meet the definition for confirmed SARS-CoV-2 infection (a positive PCR of respiratory or spinal fluid samples, serology for anti-SARS-CoV-2 IgG, or both), or the Royal College of Paediatrics and Child Health criteria for paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS). Individuals were classified as having either a primary neurological disorder associated with COVID-19 (COVID-19 neurology group) or PIMS-TS with neurological features (PIMS-TS neurology group). The denominator of all hospitalised children and adolescents with COVID-19 was collated from National Health Service England data.

Findings: Between April 2, 2020, and Feb 1, 2021, 52 cases were identified; in England, there were 51 cases among 1334 children and adolescents hospitalised with COVID-19, giving an estimated prevalence of 3·8 (95% CI 2·9-5·0) cases per 100 paediatric patients. 22 (42%) patients were female and 30 (58%) were male; the median age was 9 years (range 1-17). 36 (69%) patients were Black or Asian, 16 (31%) were White. 27 (52%) of 52 patients were classified into the COVID-19 neurology group and 25 (48%) were classified into the PIMS-TS neurology group. In the COVID-19 neurology group, diagnoses included status epilepticus (n=7), encephalitis (n=5), Guillain-Barré syndrome (n=5), acute demyelinating syndrome (n=3), chorea (n=2), psychosis (n=2), isolated encephalopathy (n=2), and transient ischaemic attack (n=1). The PIMS-TS neurology group more often had multiple features, which included encephalopathy (n=22 [88%]), peripheral nervous system involvement (n=10 [40%]), behavioural change (n=9 [36%]), and hallucinations at presentation (n=6 [24%]). Recognised neuroimmune disorders were more common in the COVID-19 neurology group than in the PIMS-TS neurology group (13 [48%] of 27 patients vs 1 [<1%] of 25 patients, p=0·0003). Compared with the COVID-19 neurology group, more patients in the PIMS-TS neurology group were admitted to intensive care (20 [80%] of 25 patients vs six [22%] of 27 patients, p=0·0001) and received immunomodulatory treatment (22 [88%] patients vs 12 [44%] patients, p=0·045). 17 (33%) patients (10 [37%] in the COVID-19 neurology group and 7 [28%] in the PIMS-TS neurology group) were discharged with disability; one (2%) died (who had stroke, in the PIMS-TS neurology group).

Interpretation: This study identified key differences between those with a primary neurological disorder versus those with PIMS-TS. Compared with patients with a primary neurological disorder, more patients with PIMS-TS needed intensive care, but outcomes were similar overall. Further studies should investigate underlying mechanisms for neurological involvement in COVID-19 and the longer-term outcomes.

Funding: UK Research and Innovation, Medical Research Council, Wellcome Trust, National Institute for Health Research.
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http://dx.doi.org/10.1016/S2352-4642(21)00193-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279959PMC
September 2021

Analysis of pediatric emergency department patient volume trends during the COVID-19 pandemic.

Medicine (Baltimore) 2021 Jul;100(27):e26583

Pediatrics, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ.

Abstract: During the early period of the COVID-19 pandemic there was a substantial decrease in pediatric emergency department (PED) visitation. The intent of this study is to report PED utilization during the COVID-19 pandemic in an urban pediatric referral center located close to the epicenter in the northeastern US.A retrospective analysis of medical records of patients visiting the PED at Robert Wood Johnson University Hospital (RWJUH) was performed. Data included: daily census, admission rate, Emergency Severity Index, and ICD-10 diagnosis codes for the period of February through July, 2018 to 2020.By the week of March 26th, visits had decreased by 70% compared to the average of the previous 2 years. This census nadir lasted for 6 weeks. At 5 weeks postnadir the average daily census recovered to levels 40% lower than prior year norms and remained at that level during subsequent months. The greatest decreases were seen in low-acuity visits. Visits for behavioral health and fractures decreased by approximately 50% and 70%, respectively, but recovered to prior year norms by June and July of 2020. Visits for asthma exacerbation decreased by as much as 87% and remained at record lows for the remainder of the study period.A substantial and persistent decrease in PED visitation was experienced during the COVID-19 pandemic. Whereas visits for behavioral health and fractures have recovered to prior year norms, visits for asthma exacerbation remain at record lows. Further research is needed to ascertain the causes of these changes, including patient perceptions of the PED.
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http://dx.doi.org/10.1097/MD.0000000000026583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270607PMC
July 2021

Accumulation of Seminolipid in Sertoli Cells Is Associated with Increased Levels of Reactive Oxygen Species and Male Subfertility: Studies in Aging Null Male Mice.

Antioxidants (Basel) 2021 Jun 4;10(6). Epub 2021 Jun 4.

Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.

Seminolipid (also known as sulfogalactosylglycerolipid-SGG), present selectively in male germ cells, plays important roles in spermatogenesis and sperm-egg interaction. The proper degradation of SGG in apoptotic germ cells is also as important. Sertoli cells first phagocytose apoptotic germ cells, then Sertoli lysosomal arylsulfatase A (ARSA) desulfates SGG, the first step of SGG degradation. We have reported that aging male mice become subfertile with SGG accumulation in Sertoli cell lysosomes, typical of a lysosomal storage disorder (LSD). Since reactive oxygen species (ROS) levels are increased in other glycolipid-accumulated LSDs, we quantified ROS in Sertoli cells. Our analyses indicated increases in superoxide and HO in Sertoli cells with elevated apoptosis rates, relative to WT counterparts. Excess HO from Sertoli cells could travel into testicular germ cells (TGCs) to induce ROS production. Our results indeed indicated higher superoxide levels in TGCs, compared with WT TGCs. Increased ROS levels in Sertoli cells and TGCs likely caused the decrease in spermatogenesis and increased the abnormal sperm population in aging mice, including the 50% decrease in sperm SGG with egg binding ability. In summary, our study indicated that increased ROS production was the mechanism through which subfertility manifested following SGG accumulation in Sertoli cells.
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http://dx.doi.org/10.3390/antiox10060912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227610PMC
June 2021

Potential for misinterpretation: An everyday problem male nurses encounter in inpatient rehabilitation.

Int J Nurs Pract 2021 Jun 11:e12985. Epub 2021 Jun 11.

Susan Wakil School of Nursing and Midwifery, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.

Aims: This study aims to report on the everyday concern of the 'potential for misinterpretation', which was the basic social problem revealed in a grounded theory study exploring male nurse practice in inpatient rehabilitation in Australia.

Background: Male nurses account for approximately 10% of nursing workforce across western countries and they practice in a range of clinical areas; however, how they practice in inpatient rehabilitation remains unexplored.

Methods: Constructivist grounded theory was used in this study and was conducted in two phases: (i) involved semi-structured interviews with 11 male nurses from October 2013 to June 2014 and (ii) observation of practice of 12 male nurses and semi-structured interviews with male nurses and 15 patients from February to April 2015.

Results: Nurse participants encountered the intersection of two pervasive patient ideologies about male nurses. Patients perceived nursing to be women's work and that male nurses are sexual threats. These two intersecting ideologies created a concern for male nurses working in inpatient rehabilitation and that concern was labelled 'potential for misinterpretation'.

Conclusion: Gender stereotypes impacted on the ability of male nurses to practise nursing in inpatient rehabilitation. Male nurses were mindful on a daily basis that misinterpretation could, and did, happen in inpatient rehabilitation.
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http://dx.doi.org/10.1111/ijn.12985DOI Listing
June 2021

Biomarkers for the Prediction and Diagnosis of Fibrostenosing Crohn's Disease: A Systematic Review.

Clin Gastroenterol Hepatol 2021 Jun 2. Epub 2021 Jun 2.

Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio; Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio.

Background And Aims: Intestinal strictures are a common complication of Crohn's disease (CD). Biomarkers of intestinal strictures would assist in their prediction, diagnosis, and monitoring. Herein we provide a comprehensive systematic review of studies assessing biomarkers that may predict or diagnose CD-associated strictures.

Methods: We performed a systematic review of PubMed, EMBASE, ISI Web of Science, Cochrane Library, and Scopus to identify citations pertaining to biomarkers of intestinal fibrosis through July 6, 2020, that used a reference standard of full-thickness histopathology or cross-sectional imaging or endoscopy. Studies were categorized based on the type of biomarker they evaluated (serum, genetic, histopathologic, or fecal).

Results: Thirty-five distinct biomarkers from 3 major groups were identified: serum (20 markers), genetic (9 markers), and histopathology (6 markers). Promising markers include cartilage oligomeric matrix protein, hepatocyte growth factor activator, and lower levels of microRNA-19-3p (area under the curves were 0.805, 0.738, and 0.67, respectively), and multiple anti-flagellin antibodies (A4-Fla2 [odds ratio, 3.41], anti Fla-X [odds ratio, 2.95], and anti-CBir1 [multiple]). Substantial heterogeneity was observed and none of the markers had undergone formal validation. Specific limitations to acceptance of these markers included failure to use a standardized definition of stricturing disease, lack of specificity, and insufficient relevance to the pathogenesis of intestinal strictures or incomplete knowledge regarding their operating properties.

Conclusions: There is a lack of well-defined studies on biomarkers of intestinal stricture. Development of reliable and accurate biomarkers of stricture is a research priority. Biomarkers can support the clinical management of CD patients and aid in the stratification and monitoring of patients during clinical trials of future antifibrotic drug candidates.
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http://dx.doi.org/10.1016/j.cgh.2021.05.054DOI Listing
June 2021

Melatonin and multiple sclerosis.

Mult Scler Relat Disord 2021 06 18;51:103032. Epub 2021 May 18.

Executive editor.

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http://dx.doi.org/10.1016/j.msard.2021.103032DOI Listing
June 2021

Non-invasive vagus nerve stimulation improves clinical and molecular biomarkers of Parkinson's disease in patients with freezing of gait.

NPJ Parkinsons Dis 2021 May 27;7(1):46. Epub 2021 May 27.

Institute of Neurosciences Kolkata, Kolkata, India.

Non-invasive vagus nerve stimulation (nVNS) is an established neurostimulation therapy used in the treatment of epilepsy, migraine and cluster headache. In this randomized, double-blind, sham-controlled crossover trial we explored the role of nVNS in the treatment of gait and other motor symptoms in Parkinson's disease (PD) patients. In a subgroup of patients, we measured selected neurotrophin levels and markers of inflammation and oxidative stress in serum, before and after the experimental intervention. Thirty-three PD patients with associated freezing of gait were randomised to either nVNS or sham. After baseline assessments, patients were instructed to deliver 6 two-minute stimulations (total 12 min/day) of the nVNS/sham device (electroCore, Inc. USA) for one month at home. Patients were then re-assessed. After a washout period of one month, the same patients were allocated to the alternate treatment arm and the same process was followed. Significant improvements in key gait parameters were observed with nVNS, including walking speed, stance time and step length, compared to sham. Similarly, overall motor function (MDS-UPDRS III) also improved significantly following nVNS stimulation. Serum Tumor Necrosis Factor (TNF)-α and glutathione levels decreased and brain-derived neurotrophic factor (BDNF) levels increased significantly (p < 0.05) after treatment with nVNS. Here we present the first double-blind sham-controlled trial evidence of the efficacy and safety of nVNS in the treatment of gait and motor function in patients with PD.
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http://dx.doi.org/10.1038/s41531-021-00190-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160211PMC
May 2021

Neurostructural and Neurophysiological Correlates of Multiple Sclerosis Physical Fatigue: Systematic Review and Meta-Analysis of Cross-Sectional Studies.

Neuropsychol Rev 2021 May 7. Epub 2021 May 7.

Department of Sport, Health & Exercise Science, University of Hull, Hull, UK.

Fatigue is one of the most debilitating symptoms for people with multiple sclerosis (PwMS). By consolidating a diverse and conflicting evidence-base, this systematic review and meta-analysis aimed to gain new insights into the neurobiology of MS fatigue. MEDLINE, ProQuest, CINAHL, Web of Science databases and grey literature were searched using Medical Subject Headings. Eligible studies compared neuroimaging and neurophysiological data between people experiencing high (MS-HF) versus low (MS-LF) levels of perceived MS fatigue, as defined by validated fatigue questionnaire cut-points. Data were available from 66 studies, with 46 used for meta-analyses. Neuroimaging studies revealed lower volumetric measures in MS-HF versus MS-LF for whole brain (-22.74 ml; 95% CI: -37.72 to -7.76 ml; p = 0.003), grey matter (-18.81 ml; 95% CI: -29.60 to -8.03 ml; p < 0.001), putamen (-0.40 ml; 95% CI: -0.69 to -0.10 ml; p = 0.008) and acumbens (-0.09 ml; 95% CI: -0.15 to -0.03 ml; p = 0.003) and a higher volume of T1-weighted hypointense lesions (1.10 ml; 95% CI: 0.47 to 1.73 ml; p < 0.001). Neurophysiological data showed reduced lower-limb maximum voluntary force production (-19.23 N; 95% CI: -35.93 to -2.53 N; p = 0.02) and an attenuation of upper-limb (-5.77%; 95% CI:-8.61 to -2.93%; p < 0.0001) and lower-limb (-2.16%; 95% CI:-4.24 to -0.07%; p = 0.04) skeletal muscle voluntary activation, accompanied by more pronounced upper-limb fatigability (-5.61%; 95% CI: -9.57 to -1.65%; p = 0.006) in MS-HF versus MS-LF. Results suggest that MS fatigue is characterised by greater cortico-subcortical grey matter atrophy and neural lesions, accompanied by neurophysiological decrements, which include reduced strength and voluntary activation. Prospero registration Prospero registration number: CRD42016017934.
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http://dx.doi.org/10.1007/s11065-021-09508-1DOI Listing
May 2021

International consensus to standardise histopathological scoring for small bowel strictures in Crohn's disease.

Gut 2021 May 5. Epub 2021 May 5.

Department of Inflammation and Immunity, Cleveland Clinic Foundation, Cleveland, Ohio, USA

Objective: Effective medical therapy and validated trial outcomes are lacking for small bowel Crohn's disease (CD) strictures. Histopathology of surgically resected specimens is the gold standard for correlation with imaging techniques. However, no validated histopathological scoring systems are currently available for small bowel stricturing disease. We convened an expert panel to evaluate the appropriateness of histopathology scoring systems and items generated based on panel opinion.

Design: Modified RAND/University of California Los Angeles methodology was used to determine the appropriateness of 313 candidate items related to assessment of CD small bowel strictures.

Results: In this exercise, diagnosis of naïve and anastomotic strictures required increased bowel wall thickness, decreased luminal diameter or internal circumference, and fibrosis of the submucosa. Specific definitions for stricture features and technical sampling parameters were also identified. Histopathologically, a stricture was defined as increased thickness of all layers of the bowel wall, fibrosis of the submucosa and bowel wall, and muscularisation of the submucosa. Active mucosal inflammatory disease was defined as neutrophilic inflammation in the lamina propria and any crypt or intact surface epithelium, erosion, ulcer and fistula. Chronic mucosal inflammatory disease was defined as crypt architectural distortion and loss, pyloric gland metaplasia, Paneth cell hyperplasia, basal lymphoplasmacytosis, plasmacytosis and fibrosis, or prominent lymphoid aggregates at the mucosa/submucosa interface. None of the scoring systems used to assess CD strictures were considered appropriate for clinical trials.

Conclusion: Standardised assessment of gross pathology and histopathology of CD small bowel strictures will improve clinical trial efficiency and aid drug development.
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http://dx.doi.org/10.1136/gutjnl-2021-324374DOI Listing
May 2021

Establishing and maintaining fertility: the importance of cell cycle arrest.

Genes Dev 2021 05 22;35(9-10):619-634. Epub 2021 Apr 22.

Priority Research Centre for Reproductive Science, School of Biomedical Science and Pharmacy, School of Environmental and Life Sciences, University of Newcastle, Callaghan, New South Wales 2308, Australia.

Development of the ovary or testis is required to establish reproductive competence. Gonad development relies on key cell fate decisions that occur early in embryonic development and are actively maintained. During gonad development, both germ cells and somatic cells proliferate extensively, a process facilitated by cell cycle regulation. This review focuses on the Cip/Kip family of cyclin-dependent kinase inhibitors (CKIs) in mouse gonad development. We particularly highlight recent single-cell RNA sequencing studies that show the heterogeneity of cyclin-dependent kinase inhibitors. This diversity highlights new roles for cell cycle inhibitors in controlling and maintaining female fertility.
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http://dx.doi.org/10.1101/gad.348151.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091977PMC
May 2021

The phenomenon of Lhermitte.

Pract Neurol 2021 Jun 13;21(3):246-248. Epub 2021 Apr 13.

Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, UK

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http://dx.doi.org/10.1136/practneurol-2020-002918DOI Listing
June 2021

Design Aspects of Doped CeO for Low-Temperature Catalytic CO Oxidation: Transient Kinetics and DFT Approach.

ACS Appl Mater Interfaces 2021 May 9;13(19):22391-22415. Epub 2021 Apr 9.

The Surface Analysis Laboratory, Faculty of Engineering and Physical Sciences, University of Surrey, Guildford GU2 4DL, U.K.

CO elimination through oxidation over highly active and cost-effective catalysts is a way forward for many processes of industrial and environmental importance. In this study, doped CeO with transition metals (TM = Cu, Co, Mn, Fe, Ni, Zr, and Zn) at a level of 20 at. % was tested for CO oxidation. The oxides were prepared using microwave-assisted sol-gel synthesis to improve catalyst's performance for the reaction of interest. The effect of heteroatoms on the physicochemical properties (structure, morphology, porosity, and reducibility) of the binary oxides M-Ce-O was meticulously investigated and correlated to their CO oxidation activity. It was found that the catalytic activity (per gram basis or TOF, s) follows the order Cu-Ce-O > Ce-Co-O > Ni-Ce-O > Mn-Ce-O > Fe-Ce-O > Ce-Zn-O > CeO. Participation of mobile lattice oxygen species in the CO/O reaction does occur, the extent of which is heteroatom-dependent. For that, state-of-the-art transient isotopic O-labeled experiments involving O/O exchange followed by step-gas CO/Ar or CO/O/Ar switches were used to quantify the contribution of lattice oxygen to the reaction. SSITKA-DRIFTS studies probed the formation of carbonates while validating the Mars-van Krevelen (MvK) mechanism. Scanning transmission electron microscopy-high-angle annular dark field imaging coupled with energy-dispersive spectroscopy proved that the elemental composition of dopants in the individual nanoparticle of ceria is less than their composition at a larger scale, allowing the assessment of the doping efficacy. Despite the similar structural features of the catalysts, a clear difference in the O mobility was also found as well as its participation (as expressed with the α descriptor) in the reaction, following the order α > α> α > α. Kinetic studies showed that it is rather the pre-exponential (entropic) factor and not the lowering of activation energy that justifies the order of activity of the solids. DFT calculations showed that the adsorption of CO on the Cu-doped CeO surface is more favorable (-16.63 eV), followed by Co, Mn, Zn (-14.46, -4.90, and -4.24 eV, respectively), and pure CeO (-0.63 eV). Also, copper compensates almost three times more charge (0.37) compared to Co and Mn, ca. 0.13 and 0.10, respectively, corroborating for its tendency to be reduced. Surface analysis (X-ray photoelectron spectroscopy), apart from the oxidation state of the elements, revealed a heteroatom-ceria surface interaction (O species) of different extents and of different populations of O species.
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http://dx.doi.org/10.1021/acsami.1c02934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153538PMC
May 2021

Use of a Recombinant Biomarker Protein DDA Library Increases DIA Coverage of Low Abundance Plasma Proteins.

J Proteome Res 2021 05 22;20(5):2374-2389. Epub 2021 Mar 22.

Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Macquarie Park, NSW 2109, Australia.

Credible detection and quantification of low abundance proteins from human blood plasma is a major challenge in precision medicine biomarker discovery when using mass spectrometry (MS). In this proof-of-concept study, we employed a mixture of selected recombinant proteins in DDA libraries to subsequently identify (not quantify) cancer-associated low abundance plasma proteins using SWATH/DIA. The exemplar DDA recombinant protein spectral library (rPSL) was derived from tryptic digestion of 36 recombinant human proteins that had been previously implicated as possible cancer biomarkers from both our own and other studies. The rPSL was then used to identify proteins from nondepleted colorectal cancer (CRC) EDTA plasmas by SWATH-MS. Most (32/36) of the proteins used in the rPSL were reliably identified from CRC plasma samples, including 8 proteins (i.e., BTC, CXCL10, IL1B, IL6, ITGB6, TGFα, TNF, TP53) not previously detected using high-stringency protein inference MS according to PeptideAtlas. The rPSL SWATH-MS protocol was compared to DDA-MS using MARS-depleted and postdigestion peptide fractionated plasmas (here referred to as a human plasma DDA library). Of the 32 proteins identified using rPSL SWATH, only 12 could be identified using DDA-MS. The 20 additional proteins exclusively identified using the rPSL SWATH approach were almost exclusively lower abundance (i.e., <10 ng/mL) proteins. To mitigate justified FDR concerns, and to replicate a more typical library creation approach, the DDA rPSL library was merged with a human plasma DDA library and SWATH identification repeated using such a merged library. The majority (33/36) of the low abundance plasma proteins added from the rPSL were still able to be identified using such a merged library when high-stringency HPP Guidelines v3.0 protein inference criteria were applied to our data set. The MS data set has been deposited to ProteomeXchange Consortium via the PRIDE partner repository (PXD022361).
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http://dx.doi.org/10.1021/acs.jproteome.0c00898DOI Listing
May 2021

Exploring predictors of HIV-1 virologic failure to long-acting cabotegravir and rilpivirine: a multivariable analysis.

AIDS 2021 07;35(9):1333-1342

ViiV Healthcare, Munich, Germany.

Objective: Efficacy and safety of long-acting cabotegravir (CAB) and rilpivirine (RPV) dosed intramuscularly every 4 or 8 weeks has been demonstrated in three Phase 3 trials. Here, factors associated with virologic failure at Week 48 were evaluated post hoc.

Design And Methods: Data from 1039 adults naive to long-acting CAB+RPV were pooled in a multivariable analysis to examine the influence of baseline viral and participant factors, dosing regimen and drug concentrations on confirmed virologic failure (CVF) occurrence using a logistic regression model. In a separate model, baseline factors statistically associated with CVF were further evaluated to understand CVF risk when present alone or in combination.

Results: Overall, 1.25% (n = 13/1039) of participants experienced CVF. Proviral RPV resistance-associated mutations (RAMs), HIV-1 subtype A6/A1, higher BMI (associated with Week 8 CAB trough concentration) and lower Week 8 RPV trough concentrations were significantly associated (P < 0.05) with increased odds of CVF (all except RPV trough are knowable at baseline). Few participants (0.4%) with zero or one baseline factor had CVF. Only a combination of at least two baseline factors (observed in 3.4%; n = 35/1039) was associated with increased CVF risk (25.7%, n = 9/35).

Conclusion: CVF is an infrequent multifactorial event, with a rate of approximately 1% in the long-acting CAB+RPV arms across Phase 3 studies (FLAIR, ATLAS and ATLAS-2M) through Week 48. Presence of at least two of proviral RPV RAMs, HIV-1 subtype A6/A1 and/or BMI at least 30 kg/m2 was associated with increased CVF risk. These findings support the use of long-acting CAB+RPV in routine clinical practice.
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http://dx.doi.org/10.1097/QAD.0000000000002883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270504PMC
July 2021

Evidence that extrapancreatic insulin production is involved in the mediation of sperm survival.

Mol Cell Endocrinol 2021 04 18;526:111193. Epub 2021 Feb 18.

Priority Research Centre for Reproductive Science, Faculty of Science and Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, 2308, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia, 2305.

Evidence is presented for expression of the insulin receptor on the surface of mammalian spermatozoa as well as transcripts for the receptor substrate adaptor proteins (IRS1-4) needed to mediate insulin action. Exposure to this hormone resulted in insulin receptor phosphorylation (pTyr972), activation of AKT (pSer473) and the stimulation of sperm motility. Intriguingly, the male germ line is also shown to be capable of generating insulin, possessing the relevant mRNA transcript and expressing strong immunocytochemical signals for both insulin and C-peptide. Insulin could be released from the spermatozoa by sonication in a concentration-dependent manner but was not secreted in response to glucose, fructose or stimulation with progesterone. However, insulin release could be induced by factors present in human uterine lavages. Furthermore, the endometrium was also shown to possess the machinery for insulin production and action (mRNA, insulin, C-peptide, proprotein convertase and insulin receptor), releasing insulin into the uterine lumen prior to ovulation. These studies emphasize the fundamental importance of extra-pancreatic insulin in regulating the reproductive process, particularly in the support of spermatozoa on their perilous voyage to the site of fertilization.
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http://dx.doi.org/10.1016/j.mce.2021.111193DOI Listing
April 2021

Development and Validation of a Novel Computed-Tomography Enterography Radiomic Approach for Characterization of Intestinal Fibrosis in Crohn's Disease.

Gastroenterology 2021 Jun 17;160(7):2303-2316.e11. Epub 2021 Feb 17.

Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China. Electronic address:

Background & Aims: No reliable method for evaluating intestinal fibrosis in Crohn's disease (CD) exists; therefore, we developed a computed-tomography enterography (CTE)-based radiomic model (RM) for characterizing intestinal fibrosis in CD.

Methods: This retrospective multicenter study included 167 CD patients with 212 bowel lesions (training, 98 lesions; test, 114 lesions) who underwent preoperative CTE and bowel resection at 1 of the 3 tertiary referral centers from January 2014 through June 2020. Bowel fibrosis was histologically classified as none-mild or moderate-severe. In the training cohort, 1454 radiomic features were extracted from venous-phase CTE and a machine learning-based RM was developed based on the reproducible features using logistic regression. The RM was validated in an independent external test cohort recruited from 3 centers. The diagnostic performance of RM was compared with 2 radiologists' visual interpretation of CTE using receiver operating characteristic (ROC) curve analysis.

Results: In the training cohort, the area under the ROC curve (AUC) of RM for distinguishing moderate-severe from none-mild intestinal fibrosis was 0.888 (95% confidence interval [CI], 0.818-0.957). In the test cohort, the RM showed robust performance across 3 centers with an AUC of 0.816 (95% CI, 0.706-0.926), 0.724 (95% CI, 0.526-0.923), and 0.750 (95% CI, 0.560-0.940), respectively. Moreover, the RM was more accurate than visual interpretations by either radiologist (radiologist 1, AUC = 0.554; radiologist 2, AUC = 0.598; both, P < .001) in the test cohort. Decision curve analysis showed that the RM provided a better net benefit to predicting intestinal fibrosis than the radiologists.

Conclusions: A CTE-based RM allows for accurate characterization of intestinal fibrosis in CD.
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http://dx.doi.org/10.1053/j.gastro.2021.02.027DOI Listing
June 2021

Exploring Bottom-Up Visual Processing and Visual Hallucinations in Parkinson's Disease With Dementia.

Front Neurol 2020 28;11:579113. Epub 2021 Jan 28.

Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.

Visual hallucinations (VH) are a common symptom of Parkinson's disease with dementia (PDD), affecting up to 65% of cases. Integrative models of their etiology posit that a decline in executive control of the visuo-perceptual system is a primary mechanism of VH generation. The role of bottom-up processing in the manifestation of VH in this condition is still not clear although visual evoked potential (VEP) differences have been associated with VH at an earlier stage of PD. Here we compared the amplitude and latency pattern reversal VEPs in healthy controls ( = 21) and PDD patients ( = 34) with a range of VH severities. PDD patients showed increased N2 latency relative to controls, but no significant differences in VEP measures were found for patients reporting complex VH (CVH) ( = 17) compared to those without VH. Our VEP findings support previous reports of declining visual system physiology in PDD and some evidence of visual system differences between patients with and without VH. However, we did not replicate previous findings of a major relationship between the integrity of the visual pathway and VH.
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http://dx.doi.org/10.3389/fneur.2020.579113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876258PMC
January 2021

MR Enterography of Complicated Crohn Disease: Stricturing and Penetrating Disease.

Top Magn Reson Imaging 2021 Feb;30(1):23-30

Department of Radiology, Cleveland Clinic Lerner College of Medicine, Cleveland, OH.

Abstract: Stricturing and penetrating disease are complications of Crohn disease (CD) that significantly affect patient outcomes. Careful evaluation for such complications is critical to the interpretation of magnetic resonance enterography. This manuscript outlines the key findings related to stricturing and penetrating CD and discusses current understanding of the pathophysiology and prognosis of complicated CD based on the literature.
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http://dx.doi.org/10.1097/RMR.0000000000000266DOI Listing
February 2021

Sensory Ganglionopathy.

N Engl J Med 2021 01;384(2):192

Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom

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http://dx.doi.org/10.1056/NEJMc2033783DOI Listing
January 2021

Semimechanistic Pharmacokinetic and Pharmacodynamic Modeling of Piperaquine in a Volunteer Infection Study with Plasmodium falciparum Blood-Stage Malaria.

Antimicrob Agents Chemother 2021 03 18;65(4). Epub 2021 Mar 18.

Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand

Dihydroartemisinin-piperaquine is a recommended first-line artemisinin combination therapy for malaria. Piperaquine is also under consideration for other antimalarial combination therapies. The aim of this study was to develop a pharmacokinetic-pharmacodynamic model that might be useful when optimizing the use of piperaquine in new antimalarial combination therapies. The pharmacokinetic-pharmacodynamic model was developed using data from a previously reported dose-ranging study where 24 healthy volunteers were inoculated with 1,800 blood-stage parasites. All volunteers received a single oral dose of piperaquine (960 mg, 640 mg, or 480 mg) on day 7 or day 8 after parasite inoculation in separate cohorts. Parasite densities were measured by quantitative PCR (qPCR), and piperaquine levels were measured in plasma samples. We used nonlinear mixed-effect modeling to characterize the pharmacokinetic properties of piperaquine and the parasite dynamics associated with piperaquine exposure. The pharmacokinetics of piperaquine was described by a three-compartment disposition model. A semimechanistic parasite dynamics model was developed to explain the maturation of parasites, sequestration of mature parasites, synchronicity of infections, and multiplication of parasites, as seen in natural clinical infections with malaria. Piperaquine-associated parasite killing was estimated using a maximum effect ( ) function. Treatment simulations (i.e., 3-day oral dosing of dihydroartemisinin-piperaquine) indicated that to be able to combat multidrug-resistant infections, an ideal additional drug in a new antimalarial triple-combination therapy should have a parasite reduction ratio of ≥10 per life cycle (38.8 h) with a duration of action of ≥2 weeks. The semimechanistic pharmacokinetic-pharmacodynamic model described here offers the potential to be a valuable tool for assessing and optimizing current and new antimalarial drug combination therapies containing piperaquine and the impact of these therapies on killing multidrug-resistant infections. (This study has been registered in the Australian and New Zealand Clinical Trials Registry under no. ANZCTRN12613000565741.).
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http://dx.doi.org/10.1128/AAC.01583-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097471PMC
March 2021

Botulinum Toxin: An Update on Pharmacology and Newer Products in Development.

Toxins (Basel) 2021 01 14;13(1). Epub 2021 Jan 14.

Department of Neurology, Institute of Neurosciences Kolkata, Kolkata 700017, India.

Since its introduction as a treatment for strabismus, botulinum toxin (BoNT) has had a phenomenal journey and is now recommended as first-line treatment for focal dystonia, despite short-term clinical benefits and the risks of adverse effects. To cater for the high demand across various medical specialties, at least six US Food and Drug Administration (FDA)-approved formulations of BoNT are currently available for diverse labelled indications. The toxo-pharmacological properties of these formulations are not uniform and thus should not be used interchangeably. Synthetic BoNTs and BoNTs from non-clostridial sources are not far from clinical use. Moreover, the study of mutations in naturally occurring toxins has led to modulation in the toxo-pharmacokinetic properties of BoNTs, including the duration and potency. We present an overview of the toxo-pharmacology of conventional and novel BoNT preparations, including those awaiting imminent translation from the laboratory to the clinic.
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http://dx.doi.org/10.3390/toxins13010058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828686PMC
January 2021

Role of Multiomics Data to Understand Host-Pathogen Interactions in COVID-19 Pathogenesis.

J Proteome Res 2021 02 11;20(2):1107-1132. Epub 2021 Jan 11.

Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India.

Human infectious diseases are contributed equally by the host immune system's efficiency and any pathogens' infectivity. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the coronavirus strain causing the respiratory pandemic coronavirus disease 2019 (COVID-19). To understand the pathobiology of SARS-CoV-2, one needs to unravel the intricacies of host immune response to the virus, the viral pathogen's mode of transmission, and alterations in specific biological pathways in the host allowing viral survival. This review critically analyzes recent research using high-throughput "omics" technologies (including proteomics and metabolomics) on various biospecimens that allow an increased understanding of the pathobiology of SARS-CoV-2 in humans. The altered biomolecule profile facilitates an understanding of altered biological pathways. Further, we have performed a meta-analysis of significantly altered biomolecular profiles in COVID-19 patients using bioinformatics tools. Our analysis deciphered alterations in the immune response, fatty acid, and amino acid metabolism and other pathways that cumulatively result in COVID-19 disease, including symptoms such as hyperglycemic and hypoxic sequelae.
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http://dx.doi.org/10.1021/acs.jproteome.0c00771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805606PMC
February 2021

Degree of Creeping Fat Assessed by Computed Tomography Enterography is Associated with Intestinal Fibrotic Stricture in Patients with Crohn's Disease: A Potentially Novel Mesenteric Creeping Fat Index.

J Crohns Colitis 2021 Jul;15(7):1161-1173

Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China.

Background And Aims: Emerging evidence points to a link between creeping fat and the pathogenesis of Crohn's disease [CD]. Non-invasive assessment of the severity of creeping fat on cross-sectional imaging modality has seldom been investigated. This study aimed to develop and characterize a novel mesenteric creeping fat index [MCFI] based on computed tomography [CT] in CD patients.

Methods: MCFI was developed based on vascular findings on CT in a retrospective cohort [n = 91] and validated in a prospective cohort [n = 30]. The severity of creeping fat was graded based on the extent to which mesenteric fat extended around the intestinal circumference using the vessels in the fat as a marker. The accuracy of MCFI was assessed by comparing it with the degree of creeping fat observed in surgical specimens. The relationship between MCFI and fibrostenosis was characterized by determining if these correlated. The accuracy of MCFI was compared with other radiographic indices [i.e. visceral to subcutaneous fat area ratio and fibrofatty proliferation score].

Results: In the retrospective cohort, MCFI had moderate accuracy in differentiating moderate-severe from mild fibrostenosis (area under the receiver operating characteristic [ROC] curve [AUC] = 0.799; p = 0.000). ROC analysis in the retrospective cohort identified a threshold MCFI of > 3 which accurately differentiated fibrostenosis severity in the prospective cohort [AUC = 0.756; p = 0.018]. An excellent correlation was shown between MCFI and the extent of fat wrapping in specimens in the prospective cohort [r = 0.840, p = 0.000]. Neither visceral to subcutaneous fat area ratio nor fibrofatty proliferation score correlated well with the degree of intestinal fibrosis.

Conclusions: MCFI can accurately characterize the extent of mesenteric fat wrapping in surgical specimens. It may become another non-invasive measure of CD fibrostenosis.
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http://dx.doi.org/10.1093/ecco-jcc/jjab005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427713PMC
July 2021

Effect of obesity on ability to lower exposure for detection of low-attenuation liver lesions.

J Appl Clin Med Phys 2021 Feb 28;22(2):138-144. Epub 2020 Dec 28.

Cleveland Clinic, Imaging Institute - Desk L10, Cleveland, OH, USA.

Purpose: The purpose of this study was to assess the effect of obesity and iterative reconstruction on the ability to reduce exposure by studying the accuracy for detection of low-contrast low-attenuation (LCLA) liver lesions on computed tomography (CT) using a phantom model.

Methods: A phantom with four unique LCLA liver lesions (5- to 15-mm spheres, -24 to -6 HU relative to 90-HU background) was scanned without ("thin" phantom) and with ("obese" phantom) a 5-cm thick fat-attenuation ring at 150 mAs (thin phantom) and 450 mAs (obese phantom) standard exposures and at 33% and 67% exposure reductions. Images were reconstructed using standard filtered back projection (FBP) and with iterative reconstruction (Adaptive Model-Based Iterative Reconstruction strength 3, ADMIRE). A noninferiority analysis of lesion detection was performed.

Results: Mean area under the curve (AUC) values for lesion detection were significantly higher for the thin phantom than for the obese phantom regardless of exposure level (P < 0.05) for both FBP and ADMIRE. At 33% exposure reduction, AUC was noninferior for both FBP and ADMIRE strength 3 (P < 0.0001). At 67% exposure reduction, AUC remained noninferior for the thin phantom (P < 0.0035), but was no longer noninferior for the obese phantom (P ≥ 0.7353). There were no statistically significant differences in AUC between FBP and ADMIRE at any exposure level for either phantom.

Conclusions: Accuracy for lesion detection was not only significantly lower in the obese phantom at all relative exposures, but detection accuracy decreased sooner while reducing the exposure in the obese phantom. There was no significant difference in lesion detection between FBP and ADMIRE at equivalent exposure levels for either phantom.
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http://dx.doi.org/10.1002/acm2.13149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882113PMC
February 2021

Prevention and Treatment of Stricturing Crohn's Disease - Perspectives and Challenges.

Expert Rev Gastroenterol Hepatol 2021 Apr 28;15(4):401-411. Epub 2020 Dec 28.

Department of Gastroenterology, Hepatology & Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.

: Fibrostenosis is a hallmark of Crohn's disease (CD), remains a challenge in today's clinical management of inflammatory bowel disease patients and represents a key event in the disease course necessitating improved preventative strategies and a multidisciplinary approach to diagnosis and management. With the advent of anti-fibrotic therapies and well-defined clinical endpoints for stricturing CD, there is promise to impact the natural history of disease.: This review summarizes current evidence in the natural history of stricturing Crohn's disease, discusses management approaches as well as future perspectives on intestinal fibrosis.: Currently, there are no specific therapies to prevent progression to fibrosis or to treat it after it becomes clinically apparent. In addition to the international effort by the Stenosis Therapy and Anti-Fibrotic Research (STAR) consortium to standardize definitions and propose endpoints in the management of stricturing CD, further research to improve our understanding of mechanisms of intestinal fibrosis will help pave the way for the development of future anti-fibrotic therapies.
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http://dx.doi.org/10.1080/17474124.2021.1854732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026566PMC
April 2021

TDP-43 proteinopathies: a new wave of neurodegenerative diseases.

J Neurol Neurosurg Psychiatry 2020 11 11. Epub 2020 Nov 11.

Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia

Inclusions of pathogenic deposits containing TAR DNA-binding protein 43 (TDP-43) are evident in the brain and spinal cord of patients that present across a spectrum of neurodegenerative diseases. For instance, the majority of patients with sporadic amyotrophic lateral sclerosis (up to 97%) and a substantial proportion of patients with frontotemporal lobar degeneration (~45%) exhibit TDP-43 positive neuronal inclusions, suggesting a role for this protein in disease pathogenesis. In addition, TDP-43 inclusions are evident in familial ALS phenotypes linked to multiple gene mutations including the TDP-43 gene coding () and unrelated genes (eg, ). While TDP-43 is an essential RNA/DNA binding protein critical for RNA-related metabolism, determining the pathophysiological mechanisms through which TDP-43 mediates neurodegeneration appears complex, and unravelling these molecular processes seems critical for the development of effective therapies. This review highlights the key physiological functions of the TDP-43 protein, while considering an expanding spectrum of neurodegenerative diseases associated with pathogenic TDP-43 deposition, and dissecting key molecular pathways through which TDP-43 may mediate neurodegeneration.
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http://dx.doi.org/10.1136/jnnp-2020-322983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803890PMC
November 2020
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