• A systematic review of resting state functional MRI connectivity changes and cognitive impairment in multiple sclerosis.

      Jandric, Danka; email: danka.jandric@manchester.ac.uk; Doshi, Anisha; email: anisha.doshi@ucl.ac.uk; Scott, Richelle; email: richelle.scott@student.manchester.ac.uk; Paling, David; email: david.paling@nhs.net; Rog, David; email: david.rog@srft.nhs.uk; Chataway, Jeremy; email: j.chataway@ucl.ac.uk; Schoonheim, Menno; email: m.schoonheim@amsterdamumc.nl; Parker, Geoff; email: geoff.parker@ucl.ac.uk; Muhlert, Nils; email: nils.muhlert@manchester.ac.uk (2021-08-12)
      Cognitive impairment in multiple sclerosis (MS) is increasingly being investigated with resting state functional MRI (rs-fMRI) functional connectivity (FC) . However, results remain difficult to interpret, showing both high and low FC associated with cognitive impairment. We conducted a systematic review of rs-fMRI studies in MS to understand whether the direction of FC change relates to cognitive dysfunction, and how this may be influenced by the choice of methodology. Embase, Medline and PsycINFO were searched for studies assessing cognitive function and rs-fMRI FC in adults with MS. Fifty-seven studies were included in a narrative synthesis. Of these, 50 found an association between cognitive impairment and FC abnormalities. Worse cognition was linked to high FC in 18 studies, and to low FC in 17 studies. Nine studies found patterns of both high and low FC related to poor cognitive performance, in different regions or for different MR metrics. There was no clear link to increased FC during early stages of MS and reduced FC in later stages, as predicted by common models of MS pathology. Throughout, we found substantial heterogeneity in study methodology, and carefully consider how this may impact on the observed findings. These results indicate an urgent need for greater standardisation in the field - in terms of the choice of MRI analysis and the definition of cognitive impairment. This will allow us to use rs-fMRI FC as a biomarker in future clinical studies, and as a tool to understand mechanisms underpinning cognitive symptoms in MS.
    • ABO Blood Groups Do Not Predict

      Francoeur, Rachel; orcid: 0000-0003-1860-4374; Atuhaire, Alon; Arinaitwe, Moses; Adriko, Moses; orcid: 0000-0001-9748-1207; Ajambo, Diana; Nankasi, Andrina; Babayan, Simon A; Lamberton, Poppy H L; orcid: 0000-0003-1048-6318 (2021-11-27)
      is a parasite which causes significant public-health issues, with over 240 million people infected globally. In Uganda alone, approximately 11.6 million people are affected. Despite over a decade of mass drug administration in this country, hyper-endemic hotspots persist, and individuals who are repeatedly heavily and rapidly reinfected are observed. Human blood-type antigens are known to play a role in the risk of infection for a variety of diseases, due to cross-reactivity between host antibodies and pathogenic antigens. There have been conflicting results on the effect of blood type on schistosomiasis infection and pathology. Moreover, the effect of blood type as a potential intrinsic host factor on prevalence, intensity, clearance, and reinfection dynamics and on co-infection risk remains unknown. Therefore, the epidemiological link between host blood type and infection dynamics was assessed in three hyper-endemic communities in Uganda. Longitudinal data incorporating repeated pretreatment infection intensities and clearance rates were used to analyse associations between blood groups in school-aged children. Soil-transmitted helminth coinfection status and biometric parameters were incorporated in a generalised linear mixed regression model including age, gender, and body mass index (BMI), which have previously been established as significant factors influencing the prevalence and intensity of schistosomiasis. The analysis revealed no associations between blood type and prevalence, infection intensity, clearance, reinfection, or coinfection. Variations in infection profiles were significantly different between the villages, and egg burden significantly decreased with age. While blood type has proven to be a predictor of several diseases, the data collected in this study indicate that it does not play a significant role in infection burdens in these high-endemicity communities.
    • About this title - Celebrating 100 Years of Female Fellowship of the Geological Society: Discovering Forgotten Histories

      Burek, C. V.; Higgs, B. M. (Geological Society of London, 2021-03-15)
      The Geological Society of London was founded in 1807. At the time, membership was restricted to men, many of whom became well-known names in the history of the geological sciences. On the 21 May 1919, the first female Fellows were elected to the Society, 112 years after its formation.This Special Publication celebrates the centenary of that important event. In doing so it presents the often untold stories of pioneering women geoscientists from across the world who navigated male-dominated academia and learned societies, experienced the harsh realities of Siberian field-exploration, or responded to the strategic necessity of the ‘petroleum girls’ in early American oil exploration and production.It uncovers important female role models in the history of science, and investigates why not all of these women received due recognition from their contemporaries and peers. The work has identified a number of common issues that sometimes led to original work and personal achievements being lost or unacknowledged, and as a consequence, to histories being unwritten.
    • Accessibility and Acceptability of Digital Healthcare Services among People Living in Southwestern Nigeria

      Okeke, Emeka Benjamin; Hessel, Franz; Ibisola, Babalola Adeniyi; Odunola, Modupe (Walter de Gruyter GmbH, 2021-09-20)
      Abstract Background: The advent of digital healthcare services has become paramount in the world we live in today. Digital healthcare involves the use of information and communication technologies in addressing the medical problems and health-related challenges faced by people seeking medical treatment. This study assesses the impact of digital healthcare among technologically literate people in Southwestern Nigeria (SWN) and seeks to understand its accessibility and acceptability among them. Methods: The study was a cross-sectional study. Our study data was obtained through an online questionnaire survey of 427 individuals (aged ≥15 years) living in SWN. The data were analyzed using the SPSS version 25 software. Results: The study found that roughly half of the respondents (52.0%) have heard about digital healthcare while only 44.0% have accessed it. Over seven-tenth (76.3%) of the respondents considered digital healthcare to be an acceptable form of receiving healthcare while 64.4% were willing to pay for it. Age (X2=7.702, p-value = 0.021), occupation (X2=20.685, p-value = 0.004) and awareness about digital healthcare (X2=55.507, p-value = 0.001) were significantly associated with accessibility of digital healthcare. Conclusion: The findings obtained from this study showed that awareness of digital healthcare was high among people in SWN; however, its accessibility was low. Also, digital healthcare was highly acceptable amongst them and they were willing to pay for such service.
    • Accuracy of emergency medical services (EMS) telephone triage in identifying acute coronary syndrome (ACS) for patients with chest pain: a systematic literature review.

      Alotaibi, Ahmed; orcid: 0000-0002-6465-2687; email: ahmed.alotaibi@postgrad.manchester.ac.uk; Alghamdi, Abdulrhman; Reynard, Charles; orcid: 0000-0002-7534-2668; Body, Richard (2021-08-25)
      To systematically appraise the available evidence to determine the accuracy of decision aids for emergency medical services (EMS) telephone triage of patients with chest pain suspected to be caused by acute coronary syndrome (ACS) or life-threatening conditions. Systematic review. Electronic searches were performed in Embase 1974, Medline 1946 and CINAHL 1937 databases from 3 March 2020 to 4 March 2020. The review included all types of original studies that included adult patients (>18 years) who called EMS with a primary complaint of chest pain and evaluated dispatch triage priority by telephone. Outcomes of interest were a final diagnosis of ACS, acute myocardial infarction or other life-threatening conditions. Two authors independently extracted data on study design, population, study period, outcome and all data for assessment of accuracy, including cross-tabulation of triage priority against the outcomes of interest. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 assessment tool. Searches identified 553 papers, of which 3 were eligible for inclusion. Those reports described the evaluation of three different prediction models with variation in the variables used to detect ACS. The overall results showed that dispatch triage tools have good sensitivity to detect ACS and life-threatening conditions, even though they are used to triage signs and symptoms rather than diagnosing the patients. On the other hand, prediction models were built to detect ACS and life-threatening conditions, and therefore, prediction models showed better sensitivity and negative predictive value than dispatch triage tools. We have identified three prediction models for telephone triage of patients with chest pain. While they have been found to have greater accuracy than standard EMS dispatch systems, prospective external validation is essential before clinical use is considered. This systematic review was pre-registered on the International prospective register of systematic reviews (PROSPERO) database (reference CRD42020171184). [Abstract copyright: © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.]
    • Addition of organic acids to acid mine drainage polluted wetland sediment leads to microbial community structure and functional changes and improved water quality.

      Aguinaga, Oscar E; White, Keith N; Dean, Andrew P; Pittman, Jon K; email: jon.pittman@manchester.ac.uk (2021-08-28)
      Acid mine drainage (AMD) is a serious environmental problem worldwide that requires efficient and sustainable remediation technologies including the use of biological mechanisms. A key challenge for AMD bioremediation is to provide optimal conditions for microbial-mediated immobilisation of trace metals. Although organic carbon and oxygen can enhance treatment efficiency, the effect on microbial communities is unclear. In this study, surface sediments from a natural wetland with proven efficiency for AMD bioremediation were artificially exposed to oxygen (by aeration) and/or organic carbon (in the form of mixed organic acids) and incubated under laboratory conditions. In addition to measuring changes in water chemistry, a metagenomics approach was used to determine changes in sediment bacterial, archaeal and fungal community structure, and functional gene abundance. The addition of organic carbon produced major changes in the abundance of microorganisms related to iron and sulfur metabolism (including Geobacter and Pelobacter) and increased levels of particulate metals via sulfate reduction. Aeration resulted in an increase in Sideroxydans abundance but no significant changes in metal chemistry were observed. The study concludes that the utilisation of organic carbon by microorganisms is more important for achieving efficient AMD treatment than the availability of oxygen, yet the combination of oxygen with organic carbon addition did not inhibit the improvements to water quality. [Abstract copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.]
    • Addition of ramucirumab or merestinib to standard first-line chemotherapy for locally advanced or metastatic biliary tract cancer: a randomised, double-blind, multicentre, phase 2 study.

      Valle, Juan W; email: juan.valle@manchester.ac.uk; Vogel, Arndt; Denlinger, Crystal S; He, Aiwu Ruth; Bai, Li-Yuan; Orlova, Rashida; Van Cutsem, Eric; Adeva, Jorge; Chen, Li-Tzong; Obermannova, Radka; et al. (2021-10)
      Biliary tract cancers are aggressive, rare, gastrointestinal malignancies with a poor prognosis; approximately half of patients with these cancers survive for less than 1 year after diagnosis with advanced disease. We aimed to evaluate the efficacy and safety of ramucirumab or merestinib in addition to first-line cisplatin-gemcitabine in patients with locally advanced or metastatic biliary tract cancer. We did a randomised, double-blind, phase 2 study at 81 hospitals across 18 countries. We enrolled patients with histologically or cytologically confirmed, non-resectable, recurrent, or metastatic biliary tract adenocarcinoma, who were treatment-naive, aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0 or 1, estimated life expectancy of 3 months or more, and measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1. Eligible participants were randomly assigned (2:1:2:1) to receive either intravenous ramucirumab 8 mg/kg or placebo (on days 1 and 8 in 21-day cycles) or oral merestinib 80 mg or placebo (once daily) until disease progression, unacceptable toxicity, death, or patient or investigator request for discontinuation. All participants received intravenous cisplatin 25 mg/m and gemcitabine 1000 mg/m (on days 1 and 8 in 21-day cycles), for a maximum of eight cycles. Randomisation was done by an interactive web response system using a permuted block method (blocks of six) and was stratified by primary tumour site, geographical region, and presence of metastatic disease. Participants, investigators, and the study funder were masked to treatment assignment within the intravenous and oral groups. The primary endpoint was investigator-assessed progression-free survival (in the intention-to-treat population). The safety analysis was done in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT02711553, and long-term follow-up is ongoing. Between May 25, 2016, and Aug 8, 2017, 450 patients were assessed for eligibility and 309 (69%) were enrolled and randomly assigned to ramucirumab (n=106), merestinib (n=102), or pooled placebo (n=101); 306 received at least one dose of study treatment. The median follow-up time for progression-free survival at data cutoff (Feb 16, 2018) was 10·9 months (IQR 8·1-14·1). Median progression-free survival was 6·5 months (80% CI 5·7-7·1) in the ramucirumab group, 7·0 months (6·2-7·1) in the merestinib group, and 6·6 months (5·6-6·8) in the pooled placebo group (ramucirumab vs placebo hazard ratio 1·12 [80% CI 0·90-1·40], two-sided stratified p=0·48; merestinib vs placebo 0·92 [0·73-1·15], two-sided stratified p=0·64). The most common grade 3 or worse adverse events were neutropenia (51 [49%] of 104 patients in the ramucirumab group; 48 [47%] of 102 in the merestinib group; and 33 [33%] of 100 in the pooled placebo group), thrombocytopenia (36 [35%]; 19 [19%]; and 17 [17%]), and anaemia (28 [27%]; 16 [16%]; and 19 [19%]). Serious adverse events occurred in 53 (51%) patients in the ramucirumab group, 56 (55%) in the merestinib group, and 48 (48%) in the pooled placebo group. Treatment-related deaths (deemed related by the investigator) occurred in one (1%) of 104 patients in the ramucirumab group (cardiac arrest) and two (2%) of 102 patients in the merestinib group (pulmonary embolism [n=1] and sepsis [n=1]). Adding ramucirumab or merestinib to first-line cisplatin-gemcitabine was well tolerated, with no new safety signals, but neither improved progression-free survival in patients with molecularly unselected, locally advanced or metastatic biliary tract cancer. The role of these targeted inhibitors remains investigational, highlighting the need for further understanding of biliary tract malignancies and the contribution of molecular selection. Eli Lilly and Company. [Abstract copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.]
    • Additively manufactured BaTiO

      Mancuso, Elena; email: e.mancuso@ulster.ac.uk; Shah, Lekha; Jindal, Swati; Serenelli, Cecile; Tsikriteas, Zois Michail; Khanbareh, Hamideh; Tirella, Annalisa; email: annalisa.tirella@manchester.ac.uk (2021-05-19)
      Piezoelectric ceramics, such as BaTiO , have gained considerable attention in bone tissue engineering applications thanks to their biocompatibility, ability to sustain a charged surface as well as improve bone cells' adhesion and proliferation. However, the poor processability and brittleness of these materials hinder the fabrication of three-dimensional scaffolds for load bearing tissue engineering applications. For the first time, this study focused on the fabrication and characterisation of BaTiO composite scaffolds by using a multi-material 3D printing technology. Polycaprolactone (PCL) was selected and used as dispersion phase for its low melting point, easy processability and wide adoption in bone tissue engineering. The proposed single-step extrusion-based strategy enabled a faster and solvent-free process, where raw materials in powder forms were mechanically mixed and subsequently fed into the 3D printing system for further processing. PCL, PCL/hydroxyapatite and PCL/BaTiO composite scaffolds were successfully produced with high level of consistency and an inner architecture made of seamlessly integrated layers. The inclusion of BaTiO ceramic particles (10% wt.) significantly improved the mechanical performance of the scaffolds (54 ± 0.5 MPa) compared to PCL/hydroxyapatite scaffolds (40.4 ± 0.1 MPa); moreover, the presence of BaTiO increased the dielectric permittivity over the entire frequency spectrum and tested temperatures. Human osteoblasts Saos-2 were seeded on scaffolds and cellular adhesion, proliferation, differentiation and deposition of bone-like extracellular matrix were evaluated. All tested scaffolds (PCL, PCL/hydroxyapatite and PCL/BaTiO ) supported cell growth and viability, preserving the characteristic cellular osteoblastic phenotype morphology, with PCL/BaTiO composite scaffolds exhibiting higher mineralisation (ALP activity) and deposited bone-like extracellular matrix (osteocalcin and collagen I). The single-step multi-material additive manufacturing technology used for the fabrication of electroactive PCL/BaTiO composite scaffolds holds great promise for sustainability (reduced material waste and manufacturing costs) and it importantly suggests PCL/BaTiO scaffolds as promising candidates for load bearing bone tissue engineering applications to solve unmet clinical needs. [Abstract copyright: Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.]
    • Adherence and a Potential Trade-Off Currently Faced in Optimizing Hemophilia Treatment

      Burke, Tom; Asghar, Sohaib; Misciattelli, Natalia; Kar, Sharmila; Morgan, George; Dhillon, Harpal; O'Hara, Jamie (American Society of Hematology, 2020-11-05)
      INTRODUCTION Severe hemophilia, i.e., <1% normal FVIII level (A) or FIX level (B), are congenital bleeding disorders characterized by uncontrolled bleeding. The clinical benefits of prophylactic FVIII/IX replacement therapy are well understood, but require adherence to a schedule of routine infusions. Optimal adherence is associated with better joint outcomes and lower rates of chronic pain. Nonetheless a lack of patient-reported data has to date limited our understanding of the patient burden associated with adherence to treatment, and the relationship between adherence and the ability to work, among people living with hemophilia in the US. Data from the Bridging Hemophilia B Experiences, Results and Opportunities into Solutions (B-HERO-S) study reported a high proportion of adults with hemophilia B receiving routine infusions (at least one infusion per month), showing a negative impact on their ability to work, and people receiving routine infusions were more likely than people treated on-demand to report an inability to work in most situations. The ability of people living with hemophilia to participate in the labor force, without barriers to job choice or working hours, is a key outcome in the drive to achieve health equity. The objective of the analysis is to examine the relationship between adherence and the labor force participation of people with severe hemophilia in the US. METHODS This analysis draws data from a patient-reported study, the 'Cost of Severe Hemophilia Across the US: A Socioeconomic Survey' (CHESS US+). Conducted in 2019, the CHESS US+ study is a cross-sectional patient-centered study of adults with severe hemophilia in the US. A patient-completed questionnaire collected data on clinical, economic, and humanistic outcomes, for a 12-month retrospective period. This analysis examines labor force participation and employment status (full-time, part-time, unemployed, retired) and chronic pain categorized by 'none', low-level ('1-5'), and high-level ('6-10'). The analysis was stratified by adherence to treatment, self-reported on a 1-10 scale, from "not at all" to "fully", categorized into low (1-6), moderate (7-9) and full (10) adherence. Results are presented as mean (standard deviation) or N (%). RESULTS The analysis comprised 356 people with severe hemophilia A (73%) and B (27%) who participated in CHESS US+ study. In Table 1, the baseline characteristics of the study population are stratified by full adherence (N = 119), moderate adherence (N=134) and low adherence (N=103). Having no chronic pain was most prevalent in the full adherence group (37.7%), compared to moderate (8.3%) or low (13.9%) adherence cohorts. Chronic pain, both low- and high-levels were least prevalent among people with full adherence. Moreover, people with low adherence were disproportionately more likely to have high-levels of chronic pain relative to moderate adherence or full adherence (Table 1). Unemployment, however, was highest in full adherence (21.1%), and people with full adherence were also least likely to be in full-time employment (42%). The full-time employment rate decreased as adherence declined from full to moderate (Table 1), and was comparable in people with low adherence (57.3%) or moderate adherence (54.5%). CONCLUSIONS This analysis of CHESS US+ examined the complex relationship between labor market outcomes and adherence to treatment, among adults with severe hemophilia in the US. Adherence was associated with lower rates of chronic pain, representing the importance of achieving an optimal treatment strategy. Nonetheless, patients achieving optimal adherence were less likely to be in full-time employment, and more likely to be part-time or unemployed, comparatively. Together, these data characterize a trade-off in clinical outcomes versus workforce participation, and suggest that the goal of achieving health equity may currently still be unmet. Disclosures Burke: HCD Economics: Current Employment; University of Chester: Current Employment; F. Hoffmann-La Roche Ltd: Consultancy. Asghar:HCD Economics: Current Employment. Misciattelli:Freeline: Current Employment, Current equity holder in publicly-traded company. Kar:Freeline: Current Employment, Current equity holder in publicly-traded company. Morgan:uniQure: Consultancy; HCD Economics: Current Employment. Dhillon:HCD Economics: Current Employment; F. Hoffmann-La Roche Ltd: Other: All authors received editorial support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. . O'Hara:HCD Economics: Current Employment, Current equity holder in private company; F. Hoffmann-La Roche Ltd: Consultancy.
    • Adherence and a Potential Trade-Off Currently Faced in Optimizing Hemophilia Treatment

      Burke, Tom; Asghar, Sohaib; Misciattelli, Natalia; Kar, Sharmila; Morgan, George; Dhillon, Harpal; O'Hara, Jamie (Elsevier, 2021-08-03)
      INTRODUCTION Severe hemophilia, i.e., <1% normal FVIII level (A) or FIX level (B), are congenital bleeding disorders characterized by uncontrolled bleeding. The clinical benefits of prophylactic FVIII/IX replacement therapy are well understood, but require adherence to a schedule of routine infusions. Optimal adherence is associated with better joint outcomes and lower rates of chronic pain. Nonetheless a lack of patient-reported data has to date limited our understanding of the patient burden associated with adherence to treatment, and the relationship between adherence and the ability to work, among people living with hemophilia in the US. Data from the Bridging Hemophilia B Experiences, Results and Opportunities into Solutions (B-HERO-S) study reported a high proportion of adults with hemophilia B receiving routine infusions (at least one infusion per month), showing a negative impact on their ability to work, and people receiving routine infusions were more likely than people treated on-demand to report an inability to work in most situations. The ability of people living with hemophilia to participate in the labor force, without barriers to job choice or working hours, is a key outcome in the drive to achieve health equity. The objective of the analysis is to examine the relationship between adherence and the labor force participation of people with severe hemophilia in the US. METHODS This analysis draws data from a patient-reported study, the ‘Cost of Severe Hemophilia Across the US: A Socioeconomic Survey’ (CHESS US+). Conducted in 2019, the CHESS US+ study is a cross-sectional patient-centered study of adults with severe hemophilia in the US. A patient-completed questionnaire collected data on clinical, economic, and humanistic outcomes, for a 12-month retrospective period. This analysis examines labor force participation and employment status (full-time, part-time, unemployed, retired) and chronic pain categorized by ‘none’, low-level ('1-5'), and high-level ('6-10'). The analysis was stratified by adherence to treatment, self-reported on a 1-10 scale, from “not at all” to “fully”, categorized into low (1-6), moderate (7-9) and full (10) adherence. Results are presented as mean (standard deviation) or N (%). RESULTS The analysis comprised 356 people with severe hemophilia A (73%) and B (27%) who participated in CHESS US+ study. In Table 1, the baseline characteristics of the study population are stratified by full adherence (N = 119), moderate adherence (N=134) and low adherence (N=103). Having no chronic pain was most prevalent in the full adherence group (37.7%), compared to moderate (8.3%) or low (13.9%) adherence cohorts. Chronic pain, both low- and high-levels were least prevalent among people with full adherence. Moreover, people with low adherence were disproportionately more likely to have high-levels of chronic pain relative to moderate adherence or full adherence (Table 1). Unemployment, however, was highest in full adherence (21.1%), and people with full adherence were also least likely to be in full-time employment (42%). The full-time employment rate decreased as adherence declined from full to moderate (Table 1), and was comparable in people with low adherence (57.3%) or moderate adherence (54.5%). CONCLUSIONS This analysis of CHESS US+ examined the complex relationship between labor market outcomes and adherence to treatment, among adults with severe hemophilia in the US. Adherence was associated with lower rates of chronic pain, representing the importance of achieving an optimal treatment strategy. Nonetheless, patients achieving optimal adherence were less likely to be in full-time employment, and more likely to be part-time or unemployed, comparatively. Together, these data characterize a trade-off in clinical outcomes versus workforce participation, and suggest that the goal of achieving health equity may currently still be unmet. Disclosures Burke: HCD Economics: Current Employment; University of Chester: Current Employment; F. Hoffmann-La Roche Ltd: Consultancy. Asghar: HCD Economics: Current Employment. Misciattelli: Freeline: Current Employment, Current equity holder in publicly-traded company. Kar: Freeline: Current Employment, Current equity holder in publicly-traded company. Morgan: uniQure: Consultancy; HCD Economics: Current Employment. Dhillon: HCD Economics: Current Employment; F. Hoffmann-La Roche Ltd: Other: All authors received editorial support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. . O'Hara: HCD Economics: Current Employment, Current equity holder in private company; F. Hoffmann-La Roche Ltd: Consultancy.
    • Adipocyte NR1D1 dictates adipose tissue expansion during obesity

      editor: Tontonoz, Peter; senior_editor: James, David E; Hunter, Ann Louise; orcid: 0000-0002-3874-4852; Pelekanou, Charlotte E; Barron, Nichola J; Northeast, Rebecca C; orcid: 0000-0002-3121-2802; Grudzien, Magdalena; Adamson, Antony D; Downton, Polly; orcid: 0000-0002-1617-6153; Cornfield, Thomas; et al. (eLife Sciences Publications, Ltd, 2021-08-05)
      The circadian clock component NR1D1 (REVERBα) is considered a dominant regulator of lipid metabolism, with global Nr1d1 deletion driving dysregulation of white adipose tissue (WAT) lipogenesis and obesity. However, a similar phenotype is not observed under adipocyte-selective deletion (Nr1d1Flox2-6:AdipoqCre), and transcriptional profiling demonstrates that, under basal conditions, direct targets of NR1D1 regulation are limited, and include the circadian clock and collagen dynamics. Under high-fat diet (HFD) feeding, Nr1d1Flox2-6:AdipoqCre mice do manifest profound obesity, yet without the accompanying WAT inflammation and fibrosis exhibited by controls. Integration of the WAT NR1D1 cistrome with differential gene expression reveals broad control of metabolic processes by NR1D1 which is unmasked in the obese state. Adipocyte NR1D1 does not drive an anticipatory daily rhythm in WAT lipogenesis, but rather modulates WAT activity in response to alterations in metabolic state. Importantly, NR1D1 action in adipocytes is critical to the development of obesity-related WAT pathology and insulin resistance.
    • Adolescents' Understanding of What Causes Emotional Distress: A Qualitative Exploration in a Non-clinical Sample Using Ideal-Type Analysis

      O'Neill, Alisha; email: alisha.oneill@Manchester.ac.uk; Stapley, Emily; Stock, Sarah; Merrick, Hannah; Humphrey, Neil (Frontiers Media S.A., 2021-05-24)
      Background: There is increased interest in early intervention and prevention of mental health difficulties during adolescence; thus, we are seeing increased efforts to optimize well-being during this epoch. Positive emotional experiences are a central component of overall well-being. However, research exploring what adolescents perceive to be the cause(s) of their emotional difficulties is lacking. Improving understanding of this issue within non-clinical adolescent groups may provide useful insight into how to develop strategies to support young people as they navigate emotional difficulties. Objectives: The aim of this research was to explore if meaningful categories of perceived cause(s) for emotional distress exist for non-clinical adolescent groups. Methods: The data for this study were drawn from interviews across 6 sites in England conducted as part of the 5-year national evaluation of the HeadStart Learning Programme. The sample comprised of 32 young people aged 11–12 years from the first annual wave of qualitative data collection in 2017. Ideal type analysis—a qualitative form of person-centered analysis—was used to construct a typology of adolescents perceived cause(s) for emotional distress. Findings: We identified five distinct categories of perceived cause: (1) perceived lack of control; (2) unfair treatment; (3) others, their actions and judgements as the catalyst; (4) concerns for self and others; and, (5) self as cause. Conclusions: Our findings illustrate that distinct categories for perceived cause of emotional distress exist among adolescents considered to be “at risk” of developing mental health difficulties, which provides a foundation for future necessary work seeking to investigate the possible link between perceived cause for emotional distress and help-seeking behavior among sub-clinical groups.
    • Adolescents’ experiences of fluctuating pain in musculoskeletal disorders: a qualitative systematic review and thematic synthesis

      Khanom, Sonia; orcid: 0000-0002-9869-2476; email: sonia.khanom@postgrad.manchester.ac.uk; McDonagh, Janet E.; Briggs, Michelle; Bakir, Ebru; McBeth, John (BioMed Central, 2020-10-02)
      Abstract: Background: Adolescents with chronic musculoskeletal pain experience daily fluctuations in pain. Although not all fluctuations are bothersome, pain flares are a distinct type of symptom fluctuation with greater impact. Since literature on the experience of pain flares is non-existent, the aim of this review was to (i) synthesise the qualitative literature on adolescents’ experiences of fluctuating pain in musculoskeletal disorders in order to (ii) identify knowledge gaps to inform future research on pain flares. Methods: Electronic databases (CINAHL, MEDLINE, EMBASE, PsycINFO), grey literature and reference lists were searched from inception to June 2018 for qualitative studies reporting adolescents’ experiences of pain. Comprehensiveness of reporting was assessed using the Consolidated Criteria for Reporting Qualitative Health Research. Studies were analysed using thematic synthesis. Results: Of the 3787 records identified, 32 studies (n = 536) were included. Principal findings were synthesised under three key themes: 1) symptom experience, 2) disruption and loss, and 3) regaining control. The first theme (symptom experience) describes adolescent’s perception and interpretation of pain fluctuations. The second theme (disruption and loss) describes the physical, social and emotional constraints faced as a result of changes in pain. The third theme (regaining control) describes coping strategies used to resist and accommodate unpredictable phases of pain. Each theme was experienced differently depending on adolescents’ characteristics such as their developmental status, pain condition, and the duration of the pain experience. Conclusions: Adolescents with chronic musculoskeletal pain live with a daily background level of symptoms which frequently fluctuate and are associated with functional and emotional difficulties. It was not clear whether these symptoms and challenges were experienced as part of ‘typical’ fluctuations in pain, or whether they reflect symptom exacerbations classified as ‘flares’. Further research is needed to explore the frequency and characteristics of pain flares, and how they differ from their typical fluctuations in pain. The review also highlights areas relating to the pain experience, symptom management and health service provision that require further exploration to support more personalised, tailored care for adolescents with chronic musculoskeletal pain.
    • Adult lifetime cost of hemophilia B management in the US: payer and societal perspectives from a decision analytic model

      Li, Nanxin; Sawyer, Eileen K.; Maruszczyk, Konrad; orcid: 0000-0002-0173-5020; Guzauskas, Greg; orcid: 0000-0002-9095-1672; Slomka, Marta T.; Burke, Tom; Martin, Antony P.; orcid: 0000-0003-4383-6038; O’Hara, Jamie; orcid: 0000-0001-8262-034X; Stevenson, Matt; orcid: 0000-0002-3099-9877; Recht, Michael; orcid: 0000-0002-2805-1016 (Informa UK Limited, 2021-03-02)
    • Adult lifetime cost of hemophilia B management in the US: Payer and societal perspectives from a decision analytic model

      Li, Nanxin; Sawyer, Eileen K.; Maruszczyk, Konrad; orcid: 0000-0002-0173-5020; Guzauskas, Greg; orcid: 0000-0002-9095-1672; Slomka, Marta T.; Burke, Tom; Martin, Antony P.; O’Hara, Jamie; Stevenson, Matt; Recht, Michael (Informa UK Limited, 2021-02-16)
    • Adult lifetime cost of hemophilia B management in the US: payer and societal perspectives from a decision analytic model

      Li, Nanxin; Sawyer, Eileen K.; Maruszczyk, Konrad; orcid: 0000-0002-0173-5020; Guzauskas, Greg; orcid: 0000-0002-9095-1672; Slomka, Marta T.; Burke, Tom; Martin, Antony P.; orcid: 0000-0003-4383-6038; O’Hara, Jamie; orcid: 0000-0001-8262-034X; Stevenson, Matt; orcid: 0000-0002-3099-9877; Recht, Michael; orcid: 0000-0002-2805-1016 (Informa UK Limited, 2021-03-02)
    • Adult lifetime cost of hemophilia B management in the US: Payer and societal perspectives from a decision analytic model.

      Li, Nanxin; Sawyer, Eileen K; Maruszczyk, Konrad; orcid: 0000-0002-0173-5020; Guzauskas, Greg; orcid: 0000-0002-9095-1672; Slomka, Marta T; Burke, Tom; Martin, Antony P; O'Hara, Jamie; Stevenson, Matt; Recht, Michael (2021-02-16)
      Hemophilia B (HB) is a rare congenital disorder characterized by bleeding-related complications which are managed by prophylactic or post-bleeding event ("on-demand") replacement of clotting factor IX (FIX). The standard of care for severe HB is life-long prophylaxis with standard half-life (SHL) or extended half-life (EHL) products given every 2-3 or 7-14 days, respectively. FIX treatment costs in the US have been investigated, but the lifetime costs of HB treatment have not been well characterized, particularly related to the impact of joint health deterioration and associated health resource utilization. We developed a decision-analytic model to explore outcomes, costs and underlying cost drivers associated with FIX treatment options over the lifetime of an adult with severe or moderately severe HB. With participation from clinicians, health technology assessment specialists and patient advocates, a Markov model was constructed to estimate bleeding events and costs associated with health states including 'bleed into joint', 'bleed not into joint', 'no bleed' and death. Sub-models of joint health were based on 0, 1, or ≥2 areas of chronic joint damage. US third-party payer and societal perspectives were considered with a lifetime horizon; sensitivity analyses tested the robustness of primary findings. Total adult lifetime costs per patient with severe and moderately severe HB were $21,086,607 for SHL FIX prophylaxis, $22,987,483 for EHL FIX prophylaxis, and $20,971,826 for on-demand FIX treatment. For FIX prophylaxis, the cost of FIX treatment account for >90% of the total HB treatment costs. This decision analytic model demonstrated significant economic burden associated with the current HB treatment paradigm.
    • Advances in Biofabrication for Tissue Engineering and Regenerative Medicine Applications

      Domingos, Marco; email: marco.domingos@manchester.ac.uk; Moxon, Sam; email: samuel.moxon@manchester.ac.uk (MDPI, 2021-05-09)
      Biofabrication strategies continue to gain considerable interest in the efforts to develop methods for better replicating in vitro models of human tissues [...]