• Bacteria and bioburden and healing in complex wounds: A prognostic systematic review

      Norman, Gill; orcid: 0000-0002-3972-5733; email: gill.norman@manchester.ac.uk; Shi, Chunhu; Westby, Maggie J.; orcid: 0000-0003-4273-3942; Price, Bianca L.; McBain, Andrew J.; Dumville, Jo C.; Cullum, Nicky (John Wiley & Sons, Inc., 2021-02-16)
      Abstract: The wound microbiome may play an important role in the wound healing process. We conducted the first systematic prognosis review investigating whether aspects of the wound microbiome are independent prognostic factors for the healing of complex wounds. We searched Medline, Embase, CINAHL and the Cochrane Library to February 2019. We included longitudinal studies which assessed the independent association of aspects of wound microbiome with healing of complex wounds while controlling for confounding factors. Two reviewers extracted data and assessed risk of bias and certainty of evidence using the GRADE approach. We synthesised studies narratively due to the clinical and methodological heterogeneity of included studies and sparse data. We identified 28 cohorts from 21 studies with a total of 38,604 participants, including people with diabetes and foot ulcers, open surgical wounds, venous leg ulcers and pressure ulcers. Risk of bias varied from low (2 cohorts) to high (17 cohorts); the great majority of participants were in cohorts at high risk of bias. Most evidence related to the association of baseline clinical wound infection with healing. Clinical infection at baseline may be associated with less likelihood of wound healing in foot ulcers in diabetes (HR from cohort with moderate risk of bias 0.53, 95% CI 0.33 to 0.83) or slower healing in open surgical wounds (HR 0.65, 95% CI 0.51 to 0.83); evidence in other wounds is more limited. Most other associations assessed showed no clear relationship with wound healing; evidence was limited and often sparse; and we documented gaps in the evidence. There is low certainty evidence that a diagnosis of wound infection may be prognostic of poorer healing in foot ulcers in diabetes, and some moderate certainty evidence for this in open surgical wounds. Low certainty evidence means that more research could change these findings.
    • Bad law or implementation flaws? Lessons from the implementation of the new law on epidemics during the response to the first wave of COVID-19 in Switzerland.

      Francetic, Igor; email: igor.francetic@manchester.ac.uk (2021-08-15)
      After the 2009-2010 H1N1 pandemic, Switzerland overhauled its 1970 law on epidemics. The reform aimed at improving early detection, surveillance, and preparedness for future outbreaks of infectious diseases. Notably, the law introduced stronger coordination between Federal and Cantonal authorities, better management tools and international cooperation. The new law entered into force in 2016 after a long legislative process. During the process, the law survived a referendum fuelled by concerns about vaccine safety and pharmaceutical industry interference. The law was first applied during the COVID-19 pandemic in early 2020. The epicentre of the outbreak in Europe was in Lombardy, a large Italian region adjacent to Switzerland and with strong economic ties with its southern region of Ticino. The first months of pandemic response highlighted two major weaknesses. Firstly, the mechanisms introduced by the new law did not ease the tension between Cantonal autonomy and central coordination of the pandemic response. Central and Cantonal authorities will need to put in place new rules and arrangements to avoid dangerous delayed responses to foreseeable problems related to the spread of infectious diseases. Secondly, relevant stakeholders excluded from the policymaking process (trade unions, firms, large industries) should be involved to allow the introduction of harsh restrictions when needed, both internally and in relation to cross-border workers. [Abstract copyright: Copyright © 2021. Published by Elsevier B.V.]
    • Bafilomycin A1 enhances NLRP3 inflammasome activation in human monocytes independent of lysosomal acidification

      Yu, Shi; Green, Jack; orcid: 0000-0003-1108-3422; Wellens, Rose; Lopez‐Castejon, Gloria; orcid: 0000-0002-8585-3381; Brough, David; orcid: 0000-0002-2250-2381; email: david.brough@manchester.ac.uk (2020-11-21)
      The release of interleukin (IL)‐1β from primary human monocytes in response to extracellular LPS occurs through the NACHT, LRR and PYD domains‐containing protein 3 (NLRP3) inflammasome. In primary monocytes, in response to LPS, NLRP3 inflammasome activation is characterized by an independence of K+ efflux and ASC speck formation and has been termed the ‘alternative’ pathway. Here, we report that pharmacological inhibition of V‐ATPase with bafilomycin A1 exacerbated LPS‐induced NLRP3 inflammasome activation in primary human monocytes. Inhibition of V‐ATPase in the presence of extracellular LPS led to NLRP3‐dependent, K+ efflux‐independent, ASC oligomerization and caspase‐1 activation. Although V‐ATPases are required for lysosomal acidification, we found that acidic lysosomal pH and protease activity were dispensable for this altered response, suggesting that V‐ATPase inhibition triggered alternative signalling events. Therefore, V‐ATPases may serve additional roles during NLRP3 inflammasome activation in primary human monocytes.
    • Balancing exploration and exploitation in public management: Proposal for an organizational model

      Palmi, Pamela; Corallo, Angelo; Prete, M. Irene; orcid: 0000-0001-9360-0475; Harris, Phil (Wiley, 2020-08-05)
    • Balancing exploration and exploitation in public management: Proposal for an organizational model

      Palmi, Pamela; Corallo, Angelo; Prete, M. Irene; orcid: 0000-0001-9360-0475; harris, Phil (Wiley, 2020-08-05)
    • ‘Banks 1 – Portugal 0’? Financial player entanglements in the Eurozone crisis

      Stadheim, Victoria B-G; orcid: 0000-0001-5801-0146; email: victoria.stadheim@winchester.ac.uk (SAGE Publications, 2020-11-01)
      The euro has been at the heart of the debate about the crisis in the Eurozone. For some, it represents a fixed exchange rate regime, which hampered peripheral countries’ competitiveness, and for others, the European Monetary Union has a ‘flawed institutional design’ and an insufficient degree of integration that engendered the crisis. The present article analyses monetary integration from a materialist perspective. It draws attention to political agency, power and crisis management. The article focuses on the case of Portugal and poses the question of how the country's authorities were compelled to request a rescue package from the International Monetary Fund, the European Central Bank and the European Commission in 2011. It shows that this decision was triggered by the political agency of a series of players within the world of finance, most notably Portugal’s domestic banks, the independent Bank of Portugal and the European Central Bank. Reflecting their material interconnection through the European monetary system, their agency was highly coordinated. The strategies for crisis management that came to deepen the recession were not the result of insufficient European integration – they rather reflected Portugal’s form of integration within the European Monetary Union at the specific moment of crisis.
    • Basil Lythgoe. 18 August 1913—18 April 2009

      Jones, J. C. (The Royal Society, 2021-03-03)
      Basil Lythgoe was distinguished as an organic chemist. He began his career at the University of Manchester, where he had studied for his undergraduate and PhD degrees, before moving to University of Cambridge. During this period he collaborated with Alexander Todd on the structural elucidation and total synthesis of the natural nucleosides, and was also noted for his investigation of the structure of the natural substance macrozamin. In 1953 he moved to the chair of organic chemistry at the University of Leeds, running a research group from which several graduate students went on to academic careers of the highest distinction. At Leeds he worked on the structure of the alkaloid taxine 1 and calciferol, among other natural substances. Lythgoe's work was characterized by a combination of insight and high experimental skill.
    • Basil Lythgoe. 18 August 1913—18 April 2009

      Jones, J. C. (The Royal Society, 2021-03-03)
      Basil Lythgoe was distinguished as an organic chemist. He began his career at the University of Manchester, where he had studied for his undergraduate and PhD degrees, before moving to University of Cambridge. During this period he collaborated with Alexander Todd on the structural elucidation and total synthesis of the natural nucleosides, and was also noted for his investigation of the structure of the natural substance macrozamin. In 1953 he moved to the chair of organic chemistry at the University of Leeds, running a research group from which several graduate students went on to academic careers of the highest distinction. At Leeds he worked on the structure of the alkaloid taxine 1 and calciferol, among other natural substances. Lythgoe's work was characterized by a combination of insight and high experimental skill.
    • Bayesian Reference Analysis for the Generalized Normal Linear Regression Model

      Tomazella, Vera Lucia Damasceno; orcid: 0000-0002-6780-2089; email: vera@ufscar.br; Jesus, Sandra Rêgo; email: sandrarj@ufba.br; Gazon, Amanda Buosi; orcid: 0000-0001-8140-5496; email: amandagazon@alumni.usp.br; Louzada, Francisco; orcid: 0000-0001-7815-9554; email: louzada@icmc.usp.br; Nadarajah, Saralees; email: saralees.nadarajah@manchester.ac.uk; Nascimento, Diego Carvalho; orcid: 0000-0002-3406-4518; email: diego.nascimento@uda.cl; Rodrigues, Francisco Aparecido; email: francisco@icmc.usp.br; Ramos, Pedro Luiz; orcid: 0000-0002-5387-2457; email: pedrolramos@usp.br (MDPI, 2021-05-12)
      This article proposes the use of the Bayesian reference analysis to estimate the parameters of the generalized normal linear regression model. It is shown that the reference prior led to a proper posterior distribution, while the Jeffreys prior returned an improper one. The inferential purposes were obtained via Markov Chain Monte Carlo (MCMC). Furthermore, diagnostic techniques based on the Kullback–Leibler divergence were used. The proposed method was illustrated using artificial data and real data on the height and diameter of Eucalyptus clones from Brazil.
    • Bedtime Oral Hygiene Behaviours, Dietary Habits and Children’s Dental Health

      Kitsaras, George; orcid: 0000-0002-1631-1730; email: georgios.kitsaras@manchester.ac.uk; Goodwin, Michaela; orcid: 0000-0002-0375-3118; email: michaela.goodwin@manchester.ac.uk; Kelly, Michael P.; orcid: 0000-0002-2029-5841; email: mk744@medschl.cam.ac.uk; Pretty, Iain A.; email: iain.a.pretty@manchester.ac.uk (MDPI, 2021-05-19)
      Background: Oral hygiene behaviours as well as dietary habits before bed can affect children’s dental health resulting in higher prevalence of dental disease. Dental disease can affect children’s health, development and even school performance. If left untreated, dental disease can progress and it can lead to extractions under general anaesthetic causing further distress for children and families. Consistent and appropriate oral hygiene behaviours and dietary habits can prevent dental diseases from occurring in the first place. Objective: This cross-sectional study examines the relationship between oral hygiene behaviours, dietary habits around bedtime and children’s dental health. Methods: A total of 185 parents with children between the ages of 3 and 7 years from deprived areas participated in the study. Data on bedtime routine activities were collected using an automated text-survey system. Children’s dental health status was established through examination of dental charts and dmft (decayed, missed, filled teeth) scores. Results: In total, 52.4% of parents reported that their children’s teeth were brushed every night. The majority of children (58.9%) had dmft scores over zero. In total, 51 (46.7% of children with dmft score over 0 and 27.5% of all children) children had active decay. The mean dmft score for those experiencing decay was 2.96 (SD = 2.22) with an overall mean dmft score of 1.75 (SD = 2.24). There were significant correlations between frequency of tooth brushing, frequency of snacks/drinks before bed and dmft scores (r = −0.584, p 0.001 and r = 0.547, p = 0.001 respectively). Finally, higher brushing frequency was associated with a lower likelihood of a dmft score greater than 0 (Exp(B) = 0.9). Conclusions: Despite families implementing oral hygiene behaviours as part of their bedtime routines those behaviours varied in their consistency. Results of this study highlight the need for additional studies that consider bedtime routine-related activities and especially the combined effects of oral hygiene practices and dietary habits due to their potentially important relationship with children’s dental health.
    • Bedtime Routine Characteristics and Activities in Families with Young Children in the North of England

      Kitsaras, George; orcid: 0000-0002-1631-1730; email: george.kitsaras@postgrad.manchester.ac.uk; Goodwin, Michaela; orcid: 0000-0002-0375-3118; email: michaela.goodwin@manchester.ac.uk; Allan, Julia; orcid: 0000-0001-7287-8363; email: j.allan@abdn.ac.uk; Kelly, Michael P.; orcid: 0000-0002-2029-5841; email: mk744@medschl.cam.ac.uk; Pretty, Iain A.; email: iain.a.pretty@manchester.ac.uk (MDPI, 2021-08-26)
      Bedtime routines have been shown to have significant associations with health, wellbeing and development outcomes for children and parents. Despite the importance of bedtime routines, most research has been carried out in the United States, with little information on bedtime routine characteristics and activities for families in other countries such as the United Kingdom and England in particular. Additionally, little is known about the possible effects of weekends vs. weekdays on the quality of bedtime routines. Finally, traditional, retrospective approaches have been most used in capturing data on bedtime routines, limiting our understanding of a dynamic and complex behaviour. The aim of this study was to explore bedtime routine characteristics and activities in families in the North of England with a real-time, dynamic data collection approach and to examine possible effects of weekend nights on the quality of bedtime routines. In total, 185 parents with children ages 3 to 7 years old provided data around their bedtime routine activities using an automated text-survey assessment over a 7-night period. Information on socio-economic and demographic characteristics were also gathered during recruitment. A small majority of parents managed to achieve all crucial elements of an optimal bedtime routine every night, with 53% reporting brushing their children’s teeth every night, 25% reading to their children every night and 30% consistently putting their children to bed at the same time each night. Results showed significant differences between weekend (especially Saturday) and weekday routines (F(1, 100) = 97.584, p 0.001), with an additional effect for parental employment (F(1, 175) = 7.151, p 0.05). Results highlight variability in bedtime routine activities and characteristics between families. Many families undertook, in a consistent manner, activities that are closely aligned with good practices and recommendations on what constitutes an optimal bedtime routine, while others struggled. Routines remained relatively stable during weekdays but showed signs of change over the weekend. Additional studies on mechanisms and elements affecting the formation, development and maintenance of bedtime routines are needed alongside studies on supporting and assisting families to achieve optimal routines.
    • Behavioural Indicators of Intra- and Inter-Specific Competition: Sheep Co-Grazing with Guanaco in the Patagonian Steppe

      Fernández, Tomás; email: tomas.fv@gmail.com; Lancaster, Alex; email: 1821496@chester.ac.uk; Moraga, Claudio A.; email: clmoraga@gmail.com; Radic-Schilling, Sergio; email: sergio.radic@umag.cl; von Hardenberg, Achaz; email: a.vonhardenberg@chester.ac.uk; Corti, Paulo; orcid: 0000-0002-8253-2195; email: pcorti@uach.cl (MDPI, 2021-11-22)
      In extensive livestock production, high densities may inhibit regulation processes, maintaining high levels of intraspecific competition over time. During competition, individuals typically modify their behaviours, particularly feeding and bite rates, which can therefore be used as indicators of competition. Over eight consecutive seasons, we investigated if variation in herd density, food availability, and the presence of a potential competitor, the guanaco (Lama guanicoe), was related with behavioural changes in domestic sheep in Chilean Patagonia. Focal sampling, instantaneous scan sampling, measures of bite and movement rates were used to quantify behavioural changes in domestic sheep. We found that food availability increased time spent feeding, while herd density was associated with an increase in vigilant behaviour and a decrease in bite rate, but only when food availability was low. Guanaco presence appeared to have no impact on sheep behaviour. Our results suggest that the observed behavioural changes in domestic sheep are more likely due to intraspecific competition rather than interspecific competition. Consideration of intraspecific competition where guanaco and sheep co-graze on pastures could allow management strategies to focus on herd density, according to rangeland carrying capacity.
    • Bempedoic Acid: The New Kid on the Block for the Treatment of Dyslipidemia and LDL Cholesterol: A Narrative Review

      Alam, Uazman; email: Uazman.alam@manchester.ac.uk; email: Uazman.alam@liverpool.ac.uk; Al-Bazz, Dalal Y.; Soran, Handrean; email: hsoran@aol.co.uk; email: Handrean.Soran@mft.nhs.uk (Springer Healthcare, 2021-05-26)
      Abstract: Diabetes is a major risk factor for atherosclerotic cardiovascular disease (ASCVD) in which dyslipidaemia plays a crucial role. Statins are first line therapy for primary and secondary prevention of ASCVD; however, adverse events include reversible musculoskeletal and liver side effects in addition to a diabetogenic association. In this short review, we provide a succinct narrative of the future role and current trial data of a novel first-in-class molecule, bempedoic acid. The authors provide their expert insight with a focus on Phase III randomised controlled trials (RCT) of bempedoic acid. Bempedoic acid was approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in February and March 2020, respectively, and is a novel molecule which inhibits cholesterol biosynthesis in the same mechanistic pathway as statins. It is a first-in-class small molecule, delivered as a prodrug and administered as an oral, once-daily dose that decreases low-density lipoprotein cholesterol (LDL-C) levels. Phase II and III RCTs have demonstrated efficacy with adequate safety data as mono- or combination therapy with statins and ezetimibe. Bempedoic acid is hepatically converted to the active drug with a lack of activation in skeletal muscle. Due to this novel mechanism, musculoskeletal-related adverse events exhibit a lower prevalence providing an alternative pharmacotherapy in statin-intolerant patients. Bempedoic acid may be used as an adjunct to diet and maximally tolerated statin therapy or in statin-intolerant patients for the treatment of dyslipidaemia. The recent National Institute of Health and Care Excellence (NICE) (UK) technology appraisal guidance [TA694] published in April 2021 recommended bempedoic acid with ezetimibe as a treatment option for primary hypercholesterolaemia or mixed dyslipidaemia if statins are not tolerated or contraindicated and if there is inadequate control of LDL-C with ezetimibe alone. Additionally, outcomes trials evaluating ‘hard’ endpoints in statin-intolerant patients or those with ASCVD are currently underway.
    • Benefits and harms of Risperidone and Paliperidone for treatment of patients with schizophrenia or bipolar disorder: a meta-analysis involving individual participant data and clinical study reports

      Hodkinson, Alexander; orcid: 0000-0003-2063-0977; email: alexander.hodkinson@manchester.ac.uk; Heneghan, Carl; Mahtani, Kamal R.; Kontopantelis, Evangelos; Panagioti, Maria (BioMed Central, 2021-08-25)
      Abstract: Background: Schizophrenia and bipolar disorder are severe mental illnesses which are highly prevalent worldwide. Risperidone and Paliperidone are treatments for either illnesses, but their efficacy compared to other antipsychotics and growing reports of hormonal imbalances continue to raise concerns. As existing evidence on both antipsychotics are solely based on aggregate data, we aimed to assess the benefits and harms of Risperidone and Paliperidone in the treatment of patients with schizophrenia or bipolar disorder, using individual participant data (IPD), clinical study reports (CSRs) and publicly available sources (journal publications and trial registries). Methods: We searched MEDLINE, Central, EMBASE and PsycINFO until December 2020 for randomised placebo-controlled trials of Risperidone, Paliperidone or Paliperidone palmitate in patients with schizophrenia or bipolar disorder. We obtained IPD and CSRs from the Yale University Open Data Access project. The primary outcome Positive and Negative Syndrome Scale (PANSS) score was analysed using one-stage IPD meta-analysis. Random-effect meta-analysis of harm outcomes involved methods for coping with rare events. Effect-sizes were compared across all available data sources using the ratio of means or relative risk. We registered our review on PROSPERO, CRD42019140556. Results: Of the 35 studies, IPD meta-analysis involving 22 (63%) studies showed a significant clinical reduction in the PANSS in patients receiving Risperidone (mean difference − 5.83, 95% CI − 10.79 to − 0.87, I2 = 8.5%, n = 4 studies, 1131 participants), Paliperidone (− 6.01, 95% CI − 8.7 to − 3.32, I2 = 4.3%, n = 13, 3821) and Paliperidone palmitate (− 7.89, 95% CI − 12.1 to − 3.69, I2 = 2.9%, n = 5, 2209). CSRs reported nearly two times more adverse events (4434 vs. 2296 publication, relative difference (RD) = 1.93, 95% CI 1.86 to 2.00) and almost 8 times more serious adverse events (650 vs. 82; RD = 7.93, 95% CI 6.32 to 9.95) than the journal publications. Meta-analyses of individual harms from CSRs revealed a significant increased risk among several outcomes including extrapyramidal disorder, tardive dyskinesia and increased weight. But the ratio of relative risk between the different data sources was not significant. Three treatment-related gynecomastia events occurred, and these were considered mild to moderate in severity. Conclusion: IPD meta-analysis conclude that Risperidone and Paliperidone antipsychotics had a small beneficial effect on reducing PANSS score over 9 weeks, which is more conservative than estimates from reviews based on journal publications. CSRs also contained significantly more data on harms that were unavailable in journal publications or trial registries. Sharing of IPD and CSRs are necessary when performing meta-analysis on the efficacy and safety of antipsychotics.
    • Benefits and harms of Risperidone and Paliperidone for treatment of patients with schizophrenia or bipolar disorder: a meta-analysis involving individual participant data and clinical study reports.

      Hodkinson, Alexander; orcid: 0000-0003-2063-0977; email: alexander.hodkinson@manchester.ac.uk; Heneghan, Carl; Mahtani, Kamal R; Kontopantelis, Evangelos; Panagioti, Maria (2021-08-25)
      <h4>Background</h4>Schizophrenia and bipolar disorder are severe mental illnesses which are highly prevalent worldwide. Risperidone and Paliperidone are treatments for either illnesses, but their efficacy compared to other antipsychotics and growing reports of hormonal imbalances continue to raise concerns. As existing evidence on both antipsychotics are solely based on aggregate data, we aimed to assess the benefits and harms of Risperidone and Paliperidone in the treatment of patients with schizophrenia or bipolar disorder, using individual participant data (IPD), clinical study reports (CSRs) and publicly available sources (journal publications and trial registries).<h4>Methods</h4>We searched MEDLINE, Central, EMBASE and PsycINFO until December 2020 for randomised placebo-controlled trials of Risperidone, Paliperidone or Paliperidone palmitate in patients with schizophrenia or bipolar disorder. We obtained IPD and CSRs from the Yale University Open Data Access project. The primary outcome Positive and Negative Syndrome Scale (PANSS) score was analysed using one-stage IPD meta-analysis. Random-effect meta-analysis of harm outcomes involved methods for coping with rare events. Effect-sizes were compared across all available data sources using the ratio of means or relative risk. We registered our review on PROSPERO, CRD42019140556.<h4>Results</h4>Of the 35 studies, IPD meta-analysis involving 22 (63%) studies showed a significant clinical reduction in the PANSS in patients receiving Risperidone (mean difference - 5.83, 95% CI - 10.79 to - 0.87, I<sup>2</sup> = 8.5%, n = 4 studies, 1131 participants), Paliperidone (- 6.01, 95% CI - 8.7 to - 3.32, I<sup>2</sup> = 4.3%, n = 13, 3821) and Paliperidone palmitate (- 7.89, 95% CI - 12.1 to - 3.69, I<sup>2</sup> = 2.9%, n = 5, 2209). CSRs reported nearly two times more adverse events (4434 vs. 2296 publication, relative difference (RD) = 1.93, 95% CI 1.86 to 2.00) and almost 8 times more serious adverse events (650 vs. 82; RD = 7.93, 95% CI 6.32 to 9.95) than the journal publications. Meta-analyses of individual harms from CSRs revealed a significant increased risk among several outcomes including extrapyramidal disorder, tardive dyskinesia and increased weight. But the ratio of relative risk between the different data sources was not significant. Three treatment-related gynecomastia events occurred, and these were considered mild to moderate in severity.<h4>Conclusion</h4>IPD meta-analysis conclude that Risperidone and Paliperidone antipsychotics had a small beneficial effect on reducing PANSS score over 9 weeks, which is more conservative than estimates from reviews based on journal publications. CSRs also contained significantly more data on harms that were unavailable in journal publications or trial registries. Sharing of IPD and CSRs are necessary when performing meta-analysis on the efficacy and safety of antipsychotics.
    • Beyond factor H: The impact of genetic-risk variants for age-related macular degeneration on circulating factor-H-like 1 and factor-H-related protein concentrations.

      Cipriani, Valentina; email: v.cipriani@qmul.ac.uk; Tierney, Anna; Griffiths, John R; Zuber, Verena; Sergouniotis, Panagiotis I; Yates, John R W; Moore, Anthony T; Bishop, Paul N; Clark, Simon J; Unwin, Richard D; email: r.unwin@manchester.ac.uk (2021-07-12)
      Age-related macular degeneration (AMD) is a leading cause of vision loss; there is strong genetic susceptibility at the complement factor H (CFH) locus. This locus encodes a series of complement regulators: factor H (FH), a splice variant factor-H-like 1 (FHL-1), and five factor-H-related proteins (FHR-1 to FHR-5), all involved in the regulation of complement factor C3b turnover. Little is known about how AMD-associated variants at this locus might influence FHL-1 and FHR protein concentrations. We have used a bespoke targeted mass-spectrometry assay to measure the circulating concentrations of all seven complement regulators and demonstrated elevated concentrations in 352 advanced AMD-affected individuals for all FHR proteins (FHR-1, p = 2.4 × 10 ; FHR-2, p = 6.0 × 10 ; FHR-3, p = 1.5 × 10 ; FHR-4, p = 1.3 × 10 ; FHR-5, p = 1.9 × 10 ) and FHL-1 (p = 4.9 × 10 ) when these individuals were compared to 252 controls, whereas no difference was seen for FH (p = 0.94). Genome-wide association analyses in controls revealed genome-wide-significant signals at the CFH locus for all five FHR proteins, and univariate Mendelian-randomization analyses strongly supported the association of FHR-1, FHR-2, FHR-4, and FHR-5 with AMD susceptibility. These findings provide a strong biochemical explanation for how genetically driven alterations in circulating FHR proteins could be major drivers of AMD and highlight the need for research into FHR protein modulation as a viable therapeutic avenue for AMD. [Abstract copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.]
    • Beyond relational continuity.

      Burch, Patrick Bm; email: patrick.burch@manchester.ac.uk (2021-07-29)