Publications by authors named "A J Sinclair"

1,290 Publications

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Dexamethasone and oxygen therapy in care home residents with diabetes: a management guide and algorithm for treatment: a rapid response action statement from the European Diabetes Working Party for Older People (EDWPOP) and European Geriatric Medicine Society (EuGMS).

Aging Clin Exp Res 2021 Apr 15. Epub 2021 Apr 15.

European Geriatric Medicine Society (EuGMS), Vienna, Austria.

This statement addresses the need to provide clinically relevant and practical guidance for long-term care staff working in care homes and other stakeholders engaged in the care of residents who require consideration for dexamethasone and oxygen therapy. It had been provided following a series of consensus discussions between the EDWPOP and the EuGMS in January and February 2021. Its main aim is to minimise morbidity and mortality from serious acute illnesses including COVID-19 requiring these treatments within the long-term care sector.
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http://dx.doi.org/10.1007/s40520-021-01822-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046642PMC
April 2021

Systemic and adipocyte transcriptional and metabolic dysregulation in Idiopathic Intracranial Hypertension.

JCI Insight 2021 Apr 13. Epub 2021 Apr 13.

Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom.

Background: Idiopathic intracranial hypertension (IIH) is a condition predominantly affecting obese women of reproductive age. Recent evidence suggests that IIH is a disease of metabolic dysregulation, androgen excess and an increased risk of cardiovascular morbidity. Here we evaluate systemic and adipose specific metabolic determinants of the IIH phenotype.

Methods: In fasted, matched IIH (N=97) and control (N=43) patients, we assessed: glucose and insulin homeostasis and leptin levels. Body composition was assessed along with an interrogation of adipose tissue function via nuclear magnetic resonance metabolomics and RNA sequencing in paired omental and subcutaneous biopsies in a case control study.

Results: We demonstrate an insulin and leptin resistant phenotype in IIH in excess to that driven by obesity. Adiposity in IIH is preferentially centripetal and is associated with increased disease activity and insulin resistance. IIH adipocytes appear transcriptionally and metabolically primed towards depot-specific lipogenesis.

Conclusions: These data show that IIH is a metabolic disorder in which adipose tissue dysfunction is a feature of the disease. Managing IIH as a metabolic disease could reduce disease morbidity and improving cardiovascular outcomes.

Funding: This study was supported by the National Institute of Health Research UK (NIHR-CS-011-028), the Medical Research Council UK (MR/K015184/1) and the Midlands Neuroscience Teaching and Research Fund.
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http://dx.doi.org/10.1172/jci.insight.145346DOI Listing
April 2021

Diabetes and Frailty: An Expert Consensus Statement on the Management of Older Adults with Type 2 Diabetes.

Diabetes Ther 2021 Apr 8. Epub 2021 Apr 8.

The Foundation for Diabetes Research in Older People (fDROP) and King's College, London, UK.

Prognosis and appropriate treatment goals for older adults with diabetes vary greatly according to frailty. It is now recognised that changes may be needed to diabetes management in some older people. Whilst there is clear guidance on the evaluation of frailty and subsequent target setting for people living with frailty, there remains a lack of formal guidance for healthcare professionals in how to achieve these targets. The management of older adults with type 2 diabetes is complicated by comorbidities, shortened life expectancy and exaggerated consequences of adverse effects from treatment. In particular, older adults are more prone to hypoglycaemia and are more vulnerable to its consequences, including falls, fractures, hospitalisation, cardiovascular events and all-cause mortality. Thus, assessment of frailty should be a routine component of a diabetes review for all older adults, and glycaemic targets and therapeutic choices should be modified accordingly. Evidence suggests that over-treatment of older adults with type 2 diabetes is common, with many having had their regimens intensified over preceding years when they were in better health, or during more recent acute hospital admissions when their blood glucose levels might have been atypically high, and nutritional intake may vary. In addition, assistance in taking medications, as often occurs in later life following implementation of community care strategies or admittance to a care home, may dramatically improve treatment adherence, leading to a fall in glycated haemoglobin (HbA1c) levels. As a person with diabetes gets older, simplification, switching or de-escalation of the therapeutic regimen may be necessary, depending on their level of frailty and HbA1c levels. Consideration should be given, in particular, to de-escalation of therapies that may induce hypoglycaemia, such as sulphonylureas and shorter-acting insulins. We discuss the use of available glucose-lowering therapies in older adults and recommend simple glycaemic management algorithms according to their level of frailty.
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http://dx.doi.org/10.1007/s13300-021-01035-9DOI Listing
April 2021

Migraine: disease characterisation, biomarkers, and precision medicine.

Lancet 2021 Apr 25;397(10283):1496-1504. Epub 2021 Mar 25.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK.

Migraine is a disabling neurological disorder, diagnosis of which is based on clinical criteria. A shortcoming of these criteria is that they do not fully capture the heterogeneity of migraine, including the underlying genetic and neurobiological factors. This complexity has generated momentum for biomarker research to improve disease characterisation and identify novel drug targets. In this Series paper, we present the progress that has been made in the search for biomarkers of migraine within genetics, provocation modelling, biochemistry, and neuroimaging research. Additionally, we outline challenges and future directions for each biomarker modality. We also discuss the advances made in combining and integrating data from multiple biomarker modalities. These efforts contribute to developing precision medicine that can be applied to future patients with migraine.
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http://dx.doi.org/10.1016/S0140-6736(20)32162-0DOI Listing
April 2021

Guiding principles for rewilding.

Conserv Biol 2021 Mar 16. Epub 2021 Mar 16.

Society for Conservation Biology, Washington, D.C., USA.

There has been much recent interest in the concept of rewilding as a tool for nature conservation, but also confusion over the idea, which has in turn limited its utility. We outline a unified definition and a series of ten guiding principles for rewilding, drawing on a global advisory group of rewilding experts. These were developed through a survey of 59 rewilding pioneers, a summary of key organisations' rewilding visions, and academic/practitioner workshops involving over 100 participants from around the world. The resulting principles are intended to clarify the concept of rewilding and to improve its effectiveness as a tool to achieve global conservation targets including actions of the UN Decade on Ecosystem Restoration and post-2020 Global Biodiversity Framework. As such we note the potential contribution of other related conservation approaches such as the IUCN CEM NbS programme. The guiding principles developed here state implicitly that rewilding sits upon a continuum of scale, connectivity, and level of human influence, and aims to restore ecosystem structure and functions to achieve a self-sustaining autonomous nature. We suggest that differences in rewilding perspectives lie largely in the extent to which this is seen as achievable, and ultimately, in those interventions which are necessary, feasible or acceptable. An understanding of the contextual setting of rewilding projects is often the key to success, and careful site-specific interpretations will be most successful at achieving the aims of rewilding. Article impact statement: Rewilding is on a continuum of scale, connectivity, and human influence and aims to restore ecosystems to achieve self-sustaining nature. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/cobi.13730DOI Listing
March 2021

Diabetes in older adults - time to include frailty as a care indicator.

Diabet Med 2021 May 23;38(5):e14560. Epub 2021 Mar 23.

Norfolk and Norwich University Hospitals NHS Foundation Trust and University of East Anglia, Norwich, UK.

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http://dx.doi.org/10.1111/dme.14560DOI Listing
May 2021

Is EBV Associated with Breast Cancer in Specific Geographic Locations?

Cancers (Basel) 2021 Feb 16;13(4). Epub 2021 Feb 16.

School of Life Sciences, University of Sussex, Brighton BN1 9 QG, UK.

Epstein-Barr virus (EBV) is a virus that establishes a life-long infection in people, and infection with EBV is nearly ubiquitous by adulthood. EBV was identified from biopsy material from a child with Burkitt's lymphoma (BL) in sub-Saharan Africa. EBV has a well-characterised role in the development of some cancers, notably, Burkitt's lymphoma (BL), Hodgkin's disease (HD), gastric carcinoma (GC), and nasopharyngeal carcinoma (NPC). Links have also been made between EBV and breast cancer (BC), but these have been controversial. For all EBV-associated cancers, the ubiquitous nature of infection with EBV, contrasted with the relatively rare development of cancer, highlights a problem of determining whether EBV is an aetiological agent of cancer. In addition, the geographic distributions of some EBV-associated cancers point to contributions from additional co-factors. Recent meta-analyses of the incidence of EBV within BC biopsies has revealed that the diversity in the conclusions remain, however, they also show more of an association between EBV and BC biopsies in some study locations. Here, we review the evidence linking EBV with BC, and conclude that the evidence for the presence of EBV in BC biopsies is concentrated in specific geographic regions but is currently insufficient to provide a causal link. We pose some questions that could help to resolve the question of whether EBV contributes to BC and probe the contribution EBV might make to the aetiology of BC.
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http://dx.doi.org/10.3390/cancers13040819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919813PMC
February 2021

Diabetes in COVID-19 pandemic-prevalence, patient characteristics and adverse outcomes.

Int J Clin Pract 2021 Feb 25:e14112. Epub 2021 Feb 25.

Foundation for Diabetes Research in Older People, Diabetes Frail Ltd, Droitwich Spa, UK.

Background: Current literature on COVID-19 pandemic has identified diabetes as a common comorbidity in patients affected. However, the evidence that diabetes increases the risk of infection, effect of diabetes on outcomes and characteristics of patients at risk is not clear.

Objectives: To explore the prevalence of diabetes in COVID-19 pandemic, effect of diabetes on clinical outcomes and to characterise the patients with diabetes affected by COVID-19.

Methods: A literature review of articles published in English language and reported outcomes on prevalence and effect of diabetes on outcomes and patients' characteristics.

Results: The prevalence of diabetes in COVID-19 patients appears similar to that in the general population. The evidence of diabetes increasing the risk of severe infection and adverse outcomes is substantial. The progression of the disease into acute respiratory distress syndrome, the requirement for intensive care admission or mechanical ventilation and mortality all have been increased by the presence of diabetes. Patients with diabetes at risk of COVID-19 appear to be obese, of older age, have uncontrolled glycaemia and have coexisting comorbidities especially cardiovascular disease and hypertension. Tight glycaemic control on admission to hospital using insulin infusion has shown some beneficial effects; however, the role of hypoglycaemic medications in the management of these patients is not yet clear.

Conclusion: High risk group should be identified and prioritised in future vaccination programmes. Future research is required to optimise management of patients with diabetes and develop new ways to manage them via technological developments such as telecare.
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http://dx.doi.org/10.1111/ijcp.14112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995213PMC
February 2021

Associations of Omega-3 fatty acids with brain morphology and volume in cognitively healthy older adults: A narrative review.

Ageing Res Rev 2021 05 16;67:101300. Epub 2021 Feb 16.

Gerontopole of Toulouse, Institute of Ageing, Toulouse University Hospital (CHU Toulouse), Toulouse, France; UPS/Inserm UMR1027, University of Toulouse III, Toulouse, France.

Introduction: Human neurodevelopment is complete by the 4th decade of life at which point brain atrophy ensues with variable rate and regionality into old age. Literally all regions of the brain experience atrophy with older age, however the pattern and rate of atrophy can dictate the behavioral consequences (i.e., cognitive impairment, Alzheimer's disease). Substantial research has aimed to discover the reasons why some people experience greater morphologic changes that produce undesirable consequences with aging and how it may be prevented. One possible explanation is diet, particularly fish consumption and the intake of omega-3 polyunsaturated fatty acids (omega 3) concentrated in fish oil. This narrative review examines the available evidence on the association between omega-3 and brain volume in non-demented older adults.

Methods: A PubMed search of the literature was conducted in search of studies that investigated the associations of omega-3 on brain morphology and volume in cognitively intact older adults. Inclusion criteria were: populations of adults aged 45 years or over, who were cognitively intact, free of any central nervous system disease, and free of advanced structural brain atrophy. Study participants had to have DHA and EPA levels measured either by blood testing or scoring of dietary intake. There were no restrictions to dates of publication. Studies including demented participants, or participants with substantial white or grey matter atrophy visible on magnetic resonance imaging were excluded.

Results And Conclusion: The search identified only 12 studies, 8 of which were cross-sectional observational studies, 3 longitudinal observational studies, and 1 randomized controlled trial published between 2007 and 2019. The largest amount of evidence indicated that the hippocampus was most frequently involved in this association, with a higher volume associated with higher omega-3 levels. Larger total grey matter, total brain volume, and lower white matter lesion volume were also associated with higher omega-3 among four of the reviewed studies. However, most studies reviewed provided mixed findings regarding the presence or absence of the association of interest, and the findings were observed to be brain region-dependent. Current evidence is still insufficient to formulate recommendations for omega-3 intake to support brain health specifically.
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http://dx.doi.org/10.1016/j.arr.2021.101300DOI Listing
May 2021

A robust machine learning framework to identify signatures for frailty: a nested case-control study in four aging European cohorts.

Geroscience 2021 Feb 18. Epub 2021 Feb 18.

CIBER of Frailty and Healthy Aging, Madrid, Spain.

Phenotype-specific omic expression patterns in people with frailty could provide invaluable insight into the underlying multi-systemic pathological processes and targets for intervention. Classical approaches to frailty have not considered the potential for different frailty phenotypes. We characterized associations between frailty (with/without disability) and sets of omic factors (genomic, proteomic, and metabolomic) plus markers measured in routine geriatric care. This study was a prevalent case control using stored biospecimens (urine, whole blood, cells, plasma, and serum) from 1522 individuals (identified as robust (R), pre-frail (P), or frail (F)] from the Toledo Study of Healthy Aging (R=178/P=184/F=109), 3 City Bordeaux (111/269/100), Aging Multidisciplinary Investigation (157/79/54) and InCHIANTI (106/98/77) cohorts. The analysis included over 35,000 omic and routine laboratory variables from robust and frail or pre-frail (with/without disability) individuals using a machine learning framework. We identified three protective biomarkers, vitamin D3 (OR: 0.81 [95% CI: 0.68-0.98]), lutein zeaxanthin (OR: 0.82 [95% CI: 0.70-0.97]), and miRNA125b-5p (OR: 0.73, [95% CI: 0.56-0.97]) and one risk biomarker, cardiac troponin T (OR: 1.25 [95% CI: 1.23-1.27]). Excluding individuals with a disability, one protective biomarker was identified, miR125b-5p (OR: 0.85, [95% CI: 0.81-0.88]). Three risks of frailty biomarkers were detected: pro-BNP (OR: 1.47 [95% CI: 1.27-1.7]), cardiac troponin T (OR: 1.29 [95% CI: 1.21-1.38]), and sRAGE (OR: 1.26 [95% CI: 1.01-1.57]). Three key frailty biomarkers demonstrated a statistical association with frailty (oxidative stress, vitamin D, and cardiovascular system) with relationship patterns differing depending on the presence or absence of a disability.
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http://dx.doi.org/10.1007/s11357-021-00334-0DOI Listing
February 2021

Headache for ophthalmologists: current advances in headache understanding and management.

Eye (Lond) 2021 Feb 12. Epub 2021 Feb 12.

Department of Neurology, University Hospitals Birmingham NHS Foundation Trust, B15 2TH, Birmingham, UK.

Patients with headache and head pain are often referred to ophthalmologists. These symptoms can either be associated with underlying ophthalmic conditions, or more often are headache disorders unrelated to the eyes. Understanding the phenotype of the headache is critical for advice, safe discharge or onward referral. This review will provide an update on the criteria for common headache disorders that are often seen by ophthalmology and embrace disorders associated with ophthalmic diseases. It will also describe the changing management of migraine and outline recent therapies that are currently available.
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http://dx.doi.org/10.1038/s41433-021-01421-4DOI Listing
February 2021

Multiple micronutrient supplementation improves micronutrient status in primary school children in Hai Phong City, Vietnam: a randomised controlled trial.

Sci Rep 2021 Feb 12;11(1):3728. Epub 2021 Feb 12.

Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Geelong, Australia.

We aimed to determine the efficacy of multiple micronutrient supplementation on the biomarkers of iron, zinc, and vitamin A status across anthropometric status categories in Vietnamese school children. In this 22-week randomised controlled trial, 347 undernourished, normal weight, or overweight/obese children aged 6-9 years were allocated to receive every school day a multiple micronutrient supplement (10 mg iron, 10 mg zinc, 400 µg vitamin A) or a placebo. Haematological indices; circulating ferritin, zinc, and retinol (corrected for inflammation); and C-reactive protein were measured at baseline and 22 weeks. At week 22, linear mixed models showed that mean corpuscular volume increased by 0.3 fL, serum ferritin by 9.1 µg/L, plasma zinc by 0.9 µmol/L, and plasma retinol by 15%, and the prevalence of zinc deficiency decreased by 17.3% points in the intervention group compared to placebo. No intervention effects were found for other haematological indices, or the prevalence of anaemia. Multiple micronutrient supplementation for 22 weeks improved the biomarkers of zinc and vitamin A status and some biomarkers of iron status, and reduced the prevalence of zinc deficiency in Vietnamese school children.Trial registration: This trial was registered on 06/09/2016 at www.anzctr.org.au as ACTRN12616001245482.
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http://dx.doi.org/10.1038/s41598-021-83129-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881239PMC
February 2021

High-strength and fibrous capsule-resistant zwitterionic elastomers.

Sci Adv 2021 Jan 1;7(1). Epub 2021 Jan 1.

Department of Chemical Engineering, University of Washington, Seattle, WA 98185, USA.

The high mechanical strength and long-term resistance to the fibrous capsule formation are two major challenges for implantable materials. Unfortunately, these two distinct properties do not come together and instead compromise each other. Here, we report a unique class of materials by integrating two weak zwitterionic hydrogels into an elastomer-like high-strength pure zwitterionic hydrogel via a "swelling" and "locking" mechanism. These zwitterionic-elastomeric-networked (ZEN) hydrogels are further shown to efficaciously resist the fibrous capsule formation upon implantation in mice for up to 1 year. Such materials with both high mechanical properties and long-term fibrous capsule resistance have never been achieved before. This work not only demonstrates a class of durable and fibrous capsule-resistant materials but also provides design principles for zwitterionic elastomeric hydrogels.
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http://dx.doi.org/10.1126/sciadv.abc5442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775767PMC
January 2021

Telemetric monitoring in idiopathic intracranial hypertension demonstrates intracranial pressure in a case with sight-threatening disease.

Acta Neurochir (Wien) 2021 03 7;163(3):725-731. Epub 2021 Jan 7.

Metabolic Neurology, Institute, of Metabolism and Systems Research, University of Birmingham, Birmingham, UK.

The understanding of raised intracranial pressure (ICP) is increasing with the directed use of intracranial telemetric ICP monitors. This case uniquely observed ICP changes by telemetric monitoring in a patient with idiopathic intracranial hypertension (IIH), who developed rapid sight-threatening disease. A lumbar drain was inserted, as a temporising measure, and was clamped prior to surgery. This resulted in a rapid rise in ICP, which normalised after insertion of a ventriculoperitoneal shunt. This case highlighted the utility of the ICP monitor and the lumbar drain as a temporising measure to control ICP prior to a definitive procedure as recommended by the IIH consensus guidelines.
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http://dx.doi.org/10.1007/s00701-020-04640-yDOI Listing
March 2021

Green Flags and headache: A concept study using the Delphi method.

Headache 2021 Feb 6;61(2):300-309. Epub 2021 Jan 6.

Department of Neurology, University Hospital Zurich, Zurich, Switzerland.

Objective: The aim of this study was to collect and rate Green Flags, that is, symptoms or pieces of information indicating that a patient is more likely to suffer from a primary than from a secondary headache.

Background: When assessing headaches, a central question to be answered is whether the pain is primary or secondary to another disorder. To maximize the likelihood of a correct diagnosis, relevant signs and symptoms must be sought, identified, and weighed against each other.

Methods: The project was designed as a Delphi study. In the first round, an expert panel proposed green flags that were rated anonymously in two subsequent rounds. Proposals with an average rating of 4.0 and higher on a scale from 0 to 5 reached consensus.

Results: Five Green Flags reached consensus: (i) "The current headache has already been present during childhood"; (ii) "The headache occurs in temporal relationship with the menstrual cycle"; (iii) "The patient has headache-free days"; (iv) "Close family members have the same headache phenotype"; and (v) "Headache occurred or stopped more than one week ago."

Conclusions: We propose five Green Flags for primary headache disorders. None being a pathognomonic sign, we recommend searching for both Green Flags and Red Flags. If both are present, a secondary headache should be suspected. Overall, the application of the Green Flag concept in clinical practice is likely to increase diagnostic accuracy and improve diagnostic resource allocation. Prospective studies in clinical populations should be conducted to validate these Green Flags.
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http://dx.doi.org/10.1111/head.14054DOI Listing
February 2021

Negative impact of COVID-19 lockdown on papilloedema and idiopathic intracranial hypertension.

J Neurol Neurosurg Psychiatry 2020 Dec 24. Epub 2020 Dec 24.

Metabolic Neurology, Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK

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http://dx.doi.org/10.1136/jnnp-2020-325519DOI Listing
December 2020

Determination of the Ultrasonic Non-linearity Parameter B/A versus Frequency for Water.

Ultrasound Med Biol 2021 Mar 7;47(3):809-819. Epub 2021 Jan 7.

Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, Ontario, Canada.

For tissue characterization, it is desirable to determine B/A using high-frequency transducers. Moreover, an accurate estimate of B/A at elevated frequencies (or at least the assumption of frequency independence of B/A) is required to evaluate the safety of high-frequency systems. However, common finite-amplitude approaches become increasingly inaccurate at high frequencies. In this article, a practical variation of the finite-amplitude method is proposed which combines experiments with numerical simulations of the Khokhlov-Zabolotskaya-Kuznetsov equation and can be used at elevated frequencies. The results at low frequencies show that the proposed approach is accurate with lower uncertainties compared with the finite-amplitude method because it avoids assumptions and approximations. The measured values of B/A versus frequency for water at 2.25-20 MHz show that there is no statistically significant variation in B/A values with frequency, and therefore the assumption of frequency independence of B/A is realistic.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2020.11.027DOI Listing
March 2021

Erenumab for headaches in idiopathic intracranial hypertension: A prospective open-label evaluation.

Headache 2021 Jan 14;61(1):157-169. Epub 2020 Dec 14.

Metabolic Neurology, Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

Objective: To determine the effectiveness of erenumab in treating headaches in idiopathic intracranial hypertension (IIH) in whom papilledema had resolved.

Background: Disability in IIH is predominantly driven by debilitating headaches with no evidence for the use of preventative therapies. Headache therapy in IIH is an urgent unmet need.

Methods: A prospective, open-label study in the United Kingdom was conducted. Adult females with confirmed diagnosis of IIH now in ocular remission (papilledema resolved) with chronic headaches (≥15 days a month) and failure of ≥3 preventative medications received erenumab 4-weekly (assessments were 3-monthly). The primary end point was change in monthly moderate/severe headache days (MmsHD) from baseline (30-day pretreatment period) compared to 12 months.

Results: Fifty-five patients, mean (SD) age 35.3 (9) years and mean duration of headaches 10.4 (8.4) years with 3.7 (0.9) preventative treatment failures, were enrolled. Mean baseline MmsHD was 16.1 (4.7) and total monthly headache days (MHD) was (29) 2.3. MmsHD reduced substantially at 12 months by mean (SD) [95% CI] 10.8 (4.0) [9.5, 11.9], p < 0.001 and MHD reduced by 13.0 (9.5) [10.2, 15.7], p < 0.001. Crystal clear days (days without any head pain) increased by 13.1 (9.5) [9.6, 15.3], p < 0.001, headache severity (scale 0-10) fell by 1.3 (1.7) [0.9, 1.9], p < 0.001, and monthly analgesic days reduced by 4.3 (9.2) [1.6, 6.9], p = 0.002. All these measures had improved significantly by 3 months, with a consistent significant response to 12 months. Headache impact test-6 score and quality of life Short Form-36 Health Survey significantly improved at 12 months. Sensitivity analysis revealed similar results for patients with and without a prior migraine diagnosis (28/55 (52%) patients) or those with or without medication overuse (27/55 (48%) patients).

Conclusions: This study provides evidence for the effectiveness of erenumab to treat headaches in IIH patients with resolution of papilledema. It provides mechanistic insights suggesting that calcitonin gene-related peptide is likely a modulator driving headache and a useful therapeutic target.
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http://dx.doi.org/10.1111/head.14026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898289PMC
January 2021

n - 3 Docosapentaenoic acid: the iceberg n - 3 fatty acid.

Curr Opin Clin Nutr Metab Care 2021 Mar;24(2):134-138

Department of Nutrition, Dietetics and Food, Monash University.

Purpose Of Review: Docosapentaenoic acid (DPA) is a minor omega-3 fatty acid (FA) which has been frequently overlooked in lipid research. This review examines the biochemical and physiological outcomes of human trials which have used pure preparations of DPA (n - 3 DPA) and also recent developments in specialized proresolving lipid mediators (SPMs) derived from n - 3 DPA.

Recent Findings: There have been only been two human studies and eleven animal studies with pure n - 3 DPA. The doses of n - 3 DPA used in the human trials have been 1-2 g/day. n - 3 DPA abundance is increased in blood lipid fractions within 3-4 days of supplementation. n - 3 DPA has the potential for unique properties, with a greater similarity in biological functioning with docosahexaenoic acid (DHA), than eicosapentaenoic acid (EPA). Despite the typically low levels of n - 3 DPA in most tissue lipids relative to EPA and DHA, unique SPMs, such as resolvins, maresins and protectins of the n - 3 DPA type, are involved in resolution of inflammation and regulating immune function.

Summary: We suggest that measurement of blood levels of n - 3 DPA gives no indication of its broad biological roles, but that the true functionality of this enigmatic n - 3 polyunsaturated fatty acid (PUFA) remains obscure until more is known about the properties of the unique DPA-derived SPMs.
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http://dx.doi.org/10.1097/MCO.0000000000000722DOI Listing
March 2021

An In Vitro Differentiation Protocol for Human Embryonic Bipotential Gonad and Testis Cell Development.

Stem Cell Reports 2020 12 19;15(6):1377-1391. Epub 2020 Nov 19.

Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, The University of Melbourne, Melbourne, Australia. Electronic address:

Currently an in vitro model that fully recapitulates the human embryonic gonad is lacking. Here we describe a fully defined feeder-free protocol to generate early testis-like cells with the ability to be cultured as an organoid, from human induced pluripotent stem cells. This stepwise approach uses small molecules to mimic embryonic development, with upregulation of bipotential gonad markers (LHX9, EMX2, GATA4, and WT1) at day 10 of culture, followed by induction of testis Sertoli cell markers (SOX9, WT1, and AMH) by day 15. Aggregation into 3D structures and extended culture on Transwell filters yielded organoids with defined tissue structures and distinct Sertoli cell marker expression. These studies provide insight into human gonadal development, suggesting that a population of precursor cells may originate from a more lateral region of the mesoderm. Our protocol represents a significant advance toward generating a much-needed human gonad organoid for studying disorders/differences of sex development.
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http://dx.doi.org/10.1016/j.stemcr.2020.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724470PMC
December 2020

A Meta-Analysis of the Impact of Professional Development on Teachers' Knowledge, Skill, and Self-Efficacy in Data-Based Decision-Making.

J Learn Disabil 2020 Nov 17:22219420970196. Epub 2020 Nov 17.

Stanford University, CA, USA.

The purpose of this review was to synthesize research on the effect of professional development (PD) targeting data-based decision-making processes on teachers' knowledge, skills, and self-efficacy related to curriculum-based measurement (CBM) and data-based decision-making (DBDM). To be eligible for this review, studies had to (a) be published in English, (b) include in-service or pre-service K-12 teachers as participants, (c) use an empirical group design, and (d) include sufficient data to calculate an effect size for teacher outcome variables. The mean effect of DBDM PD on teacher outcomes was = 0.57 ( < .001). This effect was not moderated by study quality. These results must be viewed through the lens of significant heterogeneity in effects across included studies, which could not be explained by follow-up sensitivity analyses. In addition, the experimental studies included in this review occurred under ideal, researcher-supported conditions, which impacts the generalizability of the effects of DBDM PD in practice. Implications for research and practice are discussed.
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http://dx.doi.org/10.1177/0022219420970196DOI Listing
November 2020

New horizons for idiopathic intracranial hypertension: advances and challenges.

Br Med Bull 2020 12;136(1):118-126

Metabolic Neurology, Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.

Introduction: Idiopathic intracranial hypertension (IIH) is becoming a recognized condition due to the increasing incidence linked to a global obesity epidemic.

Sources Of Data: All English papers on PubMed, Cochrane and Scholar between inception until 1 March 2020 were considered.

Areas Of Agreement: Studies suggest central adiposity has a pathogenic role. Recent weight gain is a risk factor and weight loss has a key role in management.

Areas Of Controversy: Interpretation of abnormal lumbar puncture opening pressure is debated. There is an increasing recognition of obesity stigma and how this should be approached.

Growing Points: Further evidence is required for the choice of surgical intervention for fulminant IIH. Education regarding IIH should be evidence based.

Areas Timely For Developing Research: Novel research of the pathology of IIH is influencing development of therapies such as glucagon-like peptide-1 receptor agonists and targeting unique androgen signatures. The newly discovered cardiovascular risk requires further attention.
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http://dx.doi.org/10.1093/bmb/ldaa034DOI Listing
December 2020

Anatomy of the mouse penis and internal prepuce.

Differentiation 2020 Nov - Dec;116:26-37. Epub 2020 Sep 30.

Department of Urology, University of California, 400 Parnassus Avenue, San Francisco, CA, 94143, USA.

This paper addresses a confusing issue of preputial anatomy of the mouse. The term "internal prepuce" was used in 2013 to describe a preputial structure integral to the mouse glans penis. Subsequently in 2015 the same term was applied by another group to describe entirely different morphology, generating confusion in the literature. Because it is inappropriate to use the same term to describe entirely different structures, we take this opportunity to provide further descriptive information on the internal prepuce of the mouse employing gross dissection, analysis of serial histologic section sets, three-dimensional reconstruction, scanning electron microscopy and immunohistochemistry. For this purpose, we review and illustrate the relevant literature and provide some additional new data using standard morphological techniques including immunohistochemistry. The mouse internal prepuce is integral to the glans penis and clearly is involved in sexual function in so far as it contains a major erectile body innervated by penile nerves. The development of the mouse internal prepuce is described for the first time and related to the development of the corpus cavernosum glandis.
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http://dx.doi.org/10.1016/j.diff.2020.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704899PMC
September 2020

A Comparison of Frailty Assessment Instruments in Different Clinical and Social Care Settings: The Frailtools Project.

J Am Med Dir Assoc 2021 Mar 6;22(3):607.e7-607.e12. Epub 2020 Nov 6.

Geriatrics Service, Hospital Universitario de Getafe, Madrid, Spain. Electronic address:

Objective: To determine which of 8 commonly employed frailty assessment tools demonstrate the most appropriate characteristics to be employed in different clinical and social settings.

Design: Cross-sectional multicenter European-based study.

Setting And Participants: 1440 patients aged ≥75 years evaluated in geriatric inpatient wards, geriatric outpatient clinics, primary care clinics, and nursing homes.

Methods: The frailty instruments used were Frailty Phenotype, SHARE-FI, 3-item Frailty Trait Scale (FTS-3), 5-item Frailty Trait Scale (FTS-5), FRAIL, 35-item Frailty Index (FI-35), Gérontopôle Frailty Screening Tool (GFST), and Clinical Frailty Scale (CFS). The settings were geriatrics wards, outpatient clinics, primary care, and nursing homes. Suitability was evaluated by considering the feasibility (patients with the test fully completed), administration time (time spent for administering the test), and interscale agreement (Cohen kappa index among instruments to detect frailty).

Results: The prevalence of frailty varied across settings and adopted tests. The scales with the mean highest feasibility were the FRAIL scale (99.4%), SHARE-FI (98.3%), and GFST (95.0%). The mean shortest administration times were obtained with CFS (24 seconds), GFST (72 seconds), and FRAIL scale (90 seconds). The interscale agreement between most of the tests was fair. CFS followed by FTS-5 agreed at least moderately with a greater number of scales overall and in almost all settings.

Conclusions And Implications: Based on feasibility, time to undertake the tool, and agreement with other scales, different scales would be recommended according to the setting considered. Our findings suggest that most of the tools evaluated are actually assessing different frailty constructs.
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http://dx.doi.org/10.1016/j.jamda.2020.09.024DOI Listing
March 2021

Optical coherence tomography confirms shunt malfunction and recurrence of raised intracranial pressure in optic atrophy.

Br J Neurosurg 2020 Nov 6:1-7. Epub 2020 Nov 6.

Birmingham Neuro-Ophthalmology, Queen Elizabeth Hospital, Birmingham, UK.

Background: Investigating potential cerebrospinal fluid (CSF) shunt malfunction can be a challenge. Optical coherence tomography (OCT), a non-invasive imaging technique, is used to monitor changes at the optic nerve head in papilloedema. Conventional teaching suggests that in the presence of optic atrophy the optic nerve head may not re-swell in response to a relapse in raised intracranial pressure (ICP).

Methods: A retrospective case series of three patients who had prior CSF diversion surgery for idiopathic intracranial cranial hypertension (IIH) is presented demonstrating the benefit of non-invasive OCT imaging confirming raised ICP.

Results: Recurrence of raised ICP, due to malfunctioning CSF shunt, was diagnosed in three patients requiring further surgical intervention. All re-presented acutely with headache and visual disturbances. All had a prior diagnosis of optic atrophy. In all patients, OCT peripapillary retinal nerve fibre layer qualitative image analysis and quantified progression analysis permitted easy detection of the recurrence of papilloedema.

Conclusion: OCT imaging supports clinical decision making in shunt malfunction, even in the presence of established optic atrophy secondary to IIH.
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http://dx.doi.org/10.1080/02688697.2020.1844146DOI Listing
November 2020

A Comparison of Patient-Reported Outcome Measures of Quality of Life By Dialysis Modality in the Treatment of Kidney Failure: A Systematic Review.

Can J Kidney Health Dis 2020 19;7:2054358120957431. Epub 2020 Oct 19.

The Ottawa Hospital Research Institute, The Ottawa Hospital, ON, Canada.

Background: There is an increasing demand to incorporate patient-reported outcome measures (PROMs) such as quality of life (QOL) in decision-making when selecting a chronic dialysis modality.

Objective: To compare the change in QOL over time among similar patients on different dialysis modalities to provide unique and novel insights on the impact of dialysis modality on PROMs.

Design: Systematic reviews, randomized controlled trials, and nonrandomized controlled trials were examined via a comprehensive search strategy incorporating multiple bibliographic databases.

Setting: Data were extracted from relevant studies from January 1, 2000 to December 31, 2019 without limitations on country of study conduction.

Patients: Eligible studies included adults (≥18 years) with end-stage kidney disease of any cause who were prescribed dialysis treatment (either as lifetime treatment or bridge to transplant).

Measurements: The 5 comparisons were peritoneal dialysis (PD) vs in-center hemodialysis (ICHD), home hemodialysis (HHD) vs ICHD, HHD modalities compared with one another, HHD vs PD, and self-care ICHD vs traditional nurse-based ICHD.

Methods: Included studies compared adults on different dialysis modalities with repeat measures within individuals to determine changes in QOL between dialysis modalities (in-center or home dialysis). Methodological quality was assessed by the Scottish Intercollegiate Guidelines Network (SIGN 50) checklist. A narrative synthesis was conducted, synthesizing the direction and size of any observed effects across studies.

Results: Two randomized controlled trials and 9 prospective cohort studies involving a combined total of 3711 participants were included. Comparing PD and ICHD, 5 out of 9 studies found significant differences ( < .05) favoring PD in the change of multiple QOL domains, including "physical component score," "role of social component score," "cognitive status," "role limitation due to emotional function," "role limitation due to physical function," "bodily pain," "burden of kidney disease," "effects of kidney disease on daily life," "symptoms/problems," "sexual function," "finance," and "patient satisfaction." Conversely, 3 of these studies demonstrated statistically significant differences ( < .05) favoring ICHD in the domains of "role limitation due to physical function," "general health," "support from staff," "sleep quality," "social support," "health status," "social interaction," "body image," and "overall health." Comparing HHD and ICHD, significant differences ( < .05) favoring HHD for the QOL domains of "general health," "burden of kidney disease," and the visual analogue scale were reported.

Limitations: Our study is constrained by the small sample sizes of included studies, as well as heterogeneity among both study populations and validated QOL scales, limiting inter-study comparison.

Conclusions: We identified differences in specific QOL domains between dialysis modalities that may aid in patient decision-making based on individual priorities.

Trial Registration: PROSPERO Registration Number: CRD42016046980.

Primary Funding Source: The original research for this study was derived from the Canadian Agency for Drugs and Technologies in Health (CADTH) 2017 optimal use report, titled "Dialysis Modalities for the Treatment of End-Stage Kidney Disease: A Health Technology Assessment." The CADTH receives funding from Canada's federal, provincial, and territorial governments, with the exception of Quebec.
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http://dx.doi.org/10.1177/2054358120957431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580133PMC
October 2020

11βHSD1 Inhibition with AZD4017 Improves Lipid Profiles and Lean Muscle Mass in Idiopathic Intracranial Hypertension.

J Clin Endocrinol Metab 2021 Jan;106(1):174-187

Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

Background: The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) determines prereceptor metabolism and activation of glucocorticoids within peripheral tissues. Its dysregulation has been implicated in a wide array of metabolic diseases, leading to the development of selective 11β-HSD1 inhibitors. We examined the impact of the reversible competitive 11β-HSD1 inhibitor, AZD4017, on the metabolic profile in an overweight female cohort with idiopathic intracranial hypertension (IIH).

Methods: We conducted a UK multicenter phase II randomized, double-blind, placebo-controlled trial of 12-week treatment with AZD4017. Serum markers of glucose homeostasis, lipid metabolism, renal and hepatic function, inflammation and androgen profiles were determined and examined in relation to changes in fat and lean mass by dual-energy X-ray absorptiometry.

Results: Patients receiving AZD4017 showed significant improvements in lipid profiles (decreased cholesterol, increased high-density lipoprotein [HDL] and cholesterol/HDL ratio), markers of hepatic function (decreased alkaline phosphatase and gamma-glutamyl transferase), and increased lean muscle mass (1.8%, P < .001). No changes in body mass index, fat mass, and markers of glucose metabolism or inflammation were observed. Patients receiving AZD4017 demonstrated increased levels of circulating androgens, positively correlated with changes in total lean muscle mass.

Conclusions: These beneficial metabolic changes represent a reduction in risk factors associated with raised intracranial pressure and represent further beneficial therapeutic outcomes of 11β-HSD1 inhibition by AZD4017 in this overweight IIH cohort. In particular, beneficial changes in lean muscle mass associated with AZD4017 may reflect new applications for this nature of inhibitor in the management of conditions such as sarcopenia.
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http://dx.doi.org/10.1210/clinem/dgaa766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765633PMC
January 2021

Estrogens and development of the mouse and human external genitalia.

Differentiation 2021 Mar-Apr;118:82-106. Epub 2020 Oct 1.

University of California, San Francisco, Division of Pediatric Urology, Department of Urology, 550 16th St, 5th Floor, Mission Hall Pediatric Urology, San Francisco, CA, 94158, USA.

The Jost hypothesis states that androgens are necessary for normal development of the male external genitalia. In this review, we explore the complementary hypothesis that estrogens can elicit abnormal development of male external genitalia. Herein, we review available data in both humans and mice on the deleterious effects of estrogen on external genitalia development, especially during the "window of susceptibility" to exogenous estrogens. The male and female developing external genitalia in both the human and mouse express ESR1 and ESR2, along with the androgen receptor (AR). Human clinical data suggests that exogenous estrogens can adversely affect normal penile and urethral development, resulting in hypospadias. Experimental mouse data also strongly supports the idea that exogenous estrogens cause penile and urethral defects. Despite key differences, estrogen-induced hypospadias in the mouse displays certain morphogenetic homologies to human hypospadias, including disruption of urethral fusion and preputial abnormalities. Timing of estrogenic exposure, or the "window of susceptibility," is an important consideration when examining malformations of the external genitalia in both humans and mice. In addition to a review of normal human and mouse external genital development, this article aims to review the present data on the role of estrogens in normal and abnormal development of the mouse and human internal and external genitalia. Based on the current literature for both species, we conclude that estrogen-dependent processes may play a role in abnormal genital development.
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http://dx.doi.org/10.1016/j.diff.2020.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012406PMC
October 2020

Using Optical Coherence Tomography as a Surrogate of Measurements of Intracranial Pressure in Idiopathic Intracranial Hypertension.

JAMA Ophthalmol 2020 12;138(12):1264-1271

Metabolic Neurology, Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.

Importance: There is an unmet need for noninvasive biomarkers of intracranial pressure (ICP), which manifests as papilledema that can be quantified by optical coherence tomography (OCT) imaging.

Objective: To determine whether OCT of the optic nerve head in papilledema could act as a surrogate measure of ICP.

Design, Setting, And Participants: This longitudinal cohort study used data collected from 3 randomized clinical trials that were conducted between April 1, 2014, and August 1, 2019. Participants who were female and had active idiopathic intracranial hypertension were enrolled from 5 National Health Service hospitals in the UK. Automated perimetry and OCT imaging were followed immediately by ICP measurement on the same day. Cohort 1 used continuous sitting telemetric ICP monitoring (Raumedic Neurovent P-tel device) on 1 visit. Cohort 2 was evaluated at baseline and after 3, 12, and 24 months and underwent lumbar puncture assessment of ICP.

Main Outcomes And Measures: Optical coherence tomography measures of the optic nerve head and macula were correlated with ICP levels, Frisén grading, and perimetric mean deviation. The OCT protocol included peripapillary retinal nerve fiber layer, optic nerve head, and macular volume scans (Spectralis [Heidelberg Engineering]). All scans were validated for quality and resegmented manually when required.

Results: A total of 104 women were recruited. Among cohort 1 (n = 15; mean [SD] age, 28.2 [9.4] years), the range of OCT protocols was evaluated, and optic nerve head central thickness was found to be most closely associated with ICP (right eye: r = 0.60; P = .02; left eye: r = 0.73; P = .002). Subsequently, findings from cohort 2 (n = 89; mean [SD] age, 31.8 [7.5] years) confirmed the correlation between central thickness and ICP longitudinally (12 and 24 months). Finally, bootstrap surrogacy analysis noted a positive association between central thickness and change in ICP at all points (eg, at 12 months, a decrease in central thickness of 50 μm was associated with a decrease in ICP of 5 cm H2O).

Conclusions And Relevance: In this study, optic nerve head volume measures on OCT (particularly central thickness) reproducibly correlated with ICP and surrogacy analysis demonstrated its ability to inform ICP changes. These data suggest that OCT has the utility to not only monitor papilledema but also noninvasively prognosticate ICP levels in idiopathic intracranial hypertension.
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http://dx.doi.org/10.1001/jamaophthalmol.2020.4242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582233PMC
December 2020