• A consideration of publication-derived immune-related associations in Coronavirus and related lung damaging diseases

      Geifman, Nophar; orcid: 0000-0003-2956-6676; email: nophar.geifman@manchester.ac.uk; Whetton, Anthony D. (BioMed Central, 2020-08-03)
      Abstract: Background: The severe acute respiratory syndrome virus SARS-CoV-2, a close relative of the SARS-CoV virus, is the cause of the recent COVID-19 pandemic affecting, to date, over 14 million individuals across the globe and demonstrating relatively high rates of infection and mortality. A third virus, the H5N1, responsible for avian influenza, has caused infection with some clinical similarities to those in COVID-19 infections. Cytokines, small proteins that modulate immune responses, have been directly implicated in some of the severe responses seen in COVID-19 patients, e.g. cytokine storms. Understanding the immune processes related to COVID-19, and other similar infections, could help identify diagnostic markers and therapeutic targets. Methods: Here we examine data of cytokine, immune cell types, and disease associations captured from biomedical literature associated with COVID-19, Coronavirus in general, SARS, and H5N1 influenza, with the objective of identifying potentially useful relationships and areas for future research. Results: Cytokine and cell-type associations captured from Medical Subject Heading (MeSH) terms linked to thousands of PubMed records, has identified differing patterns of associations between the four corpuses of publications (COVID-19, Coronavirus, SARS, or H5N1 influenza). Clustering of cytokine-disease co-occurrences in the context of Coronavirus has identified compelling clusters of co-morbidities and symptoms, some of which already known to be linked to COVID-19. Finally, network analysis identified sub-networks of cytokines and immune cell types associated with different manifestations, co-morbidities and symptoms of Coronavirus, SARS, and H5N1. Conclusion: Systematic review of research in medicine is essential to facilitate evidence-based choices about health interventions. In a fast moving pandemic the approach taken here will identify trends and enable rapid comparison to the literature of related diseases.
    • A psychological intervention for suicide applied to non-affective psychosis: the CARMS (Cognitive AppRoaches to coMbatting Suicidality) randomised controlled trial protocol

      Gooding, Patricia A.; orcid: 0000-0002-7458-4462; email: patricia.gooding@manchester.ac.uk; Pratt, Daniel; Awenat, Yvonne; Drake, Richard; Elliott, Rachel; Emsley, Richard; Huggett, Charlotte; Jones, Steven; Kapur, Navneet; Lobban, Fiona; et al. (BioMed Central, 2020-06-16)
      Abstract: Background: Suicide is a leading cause of death globally. Suicide deaths are elevated in those experiencing severe mental health problems, including schizophrenia. Psychological talking therapies are a potentially effective means of alleviating suicidal thoughts, plans, and attempts. However, talking therapies need to i) focus on suicidal experiences directly and explicitly, and ii) be based on testable psychological mechanisms. The Cognitive AppRoaches to coMbatting Suicidality (CARMS) project is a Randomised Controlled Trial (RCT) which aims to investigate both the efficacy and the underlying mechanisms of a psychological talking therapy for people who have been recently suicidal and have non-affective psychosis. Methods: The CARMS trial is a two-armed single-blind RCT comparing a psychological talking therapy (Cognitive Behavioural Suicide Prevention for psychosis [CBSPp]) plus Treatment As Usual (TAU) with TAU alone. There are primary and secondary suicidality outcome variables, plus mechanistic, clinical, and health economic outcomes measured over time. The primary outcome is a measure of suicidal ideation at 6 months after baseline. The target sample size is 250, with approximately 125 randomised to each arm of the trial, and an assumption of up to 25% attrition. Hence, the overall recruitment target is up to 333. An intention to treat analysis will be used with primary stratification based on National Health Service (NHS) recruitment site and antidepressant prescription medication. Recruitment will be from NHS mental health services in the North West of England, UK. Participants must be 18 or over; be under the care of mental health services; have mental health problems which meet ICD-10 non-affective psychosis criteria; and have experienced self-reported suicidal thoughts, plans, and/or attempts in the 3 months prior to recruitment. Nested qualitative work will investigate the pathways to suicidality, experiences of the therapy, and identify potential implementation challenges beyond a trial setting as perceived by numerous stake-holders. Discussion: This trial has important implications for countering suicidal experiences for people with psychosis. It will provide definitive evidence about the efficacy of the CBSPp therapy; the psychological mechanisms which lead to suicidal experiences; and provide an understanding of what is required to implement the intervention into services should it be efficacious. Trial registration: ClinicalTrials.gov (NCT03114917), 14th April 2017. ISRCTN (reference ISRCTN17776666 https://doi.org/10.1186/ISRCTN17776666); 5th June 2017). Registration was recorded prior to participant recruitment commencing.
    • A qualitative exploration of pharmacovigilance policy implementation in Jordan, Oman, and Kuwait using Matland’s ambiguity-conflict model

      Garashi, Hamza Y.; email: hamza.garashi@postgrad.manchester.ac.uk; Steinke, Douglas T.; Schafheutle, Ellen I. (BioMed Central, 2021-08-30)
      Abstract: Background: As Arab countries seek to implement the ‘Guideline on Good Pharmacovigilance Practice (GVP) for Arab countries’, understanding policy implementation mechanisms and the factors impacting it can inform best implementation practice. This study aimed to explore the mechanisms of and factors influencing pharmacovigilance policy implementation in Arab countries with more established pharmacovigilance systems (Jordan, Oman), to inform policy implementation in a country with a nascent pharmacovigilance system (Kuwait). Results: Matland’s ambiguity-conflict model served to frame data analysis from 56 face-to-face interviews, which showed that policy ambiguity and conflict were low in Jordan and Oman, suggesting an “administrative implementation” pathway. In Kuwait, policy ambiguity was high while sentiments about policy conflict were varied, suggesting a mixture between “experimental implementation” and “symbolic implementation”. Factors reducing policy ambiguity in Jordan and Oman included: decision-makers’ guidance to implementors, stakeholder involvement in the policy’s development and implementation, training of policy implementors throughout the implementation process, clearly outlined policy goals and means, and presence of a strategic implementation plan with appropriate timelines as well as a monitoring mechanism. In contrast, policy ambiguity in Kuwait stemmed from the absence or lack of attention to these factors. Factors reducing policy conflict included: the policy’s compliance with internationally recognised standards and the policy’s fit with local capabilities (all three countries), decision-makers’ cooperation with and support of the national centre as well as stakeholders’ agreement on policy goals and means (Jordan and Oman) and adopting a stepwise approach to implementation (Jordan). Conclusions: Using Matland’s model, both the mechanism of and factors impacting successful pharmacovigilance policy implementation were identified. This informed recommendations for best implementation practice in Arab as well as other countries with nascent pharmacovigilance systems, including increased managerial engagement and support, greater stakeholder involvement in policy development and implementation, and undertaking more detailed implementation planning.
    • A review of the use of propensity score diagnostics in papers published in high-ranking medical journals

      Granger, Emily; orcid: 0000-0003-0134-1467; email: emily.granger-2@postgrad.manchester.ac.uk; Watkins, Tim; Sergeant, Jamie C.; Lunt, Mark (BioMed Central, 2020-05-27)
      Abstract: Background: Propensity scores are widely used to deal with confounding bias in medical research. An incorrectly specified propensity score model may lead to residual confounding bias; therefore it is essential to use diagnostics to assess propensity scores in a propensity score analysis. The current use of propensity score diagnostics in the medical literature is unknown. The objectives of this study are to (1) assess the use of propensity score diagnostics in medical studies published in high-ranking journals, and (2) assess whether the use of propensity score diagnostics differs between studies (a) in different research areas and (b) using different propensity score methods. Methods: A PubMed search identified studies published in high-impact journals between Jan 1st 2014 and Dec 31st 2016 using propensity scores to answer an applied medical question. From each study we extracted information regarding how propensity scores were assessed and which propensity score method was used. Research area was defined using the journal categories from the Journal Citations Report. Results: A total of 894 papers were included in the review. Of these, 187 (20.9%) failed to report whether the propensity score had been assessed. Commonly reported diagnostics were p-values from hypothesis tests (36.6%) and the standardised mean difference (34.6%). Statistical tests provided marginally stronger evidence for a difference in diagnostic use between studies in different research areas (p = 0.033) than studies using different propensity score methods (p = 0.061). Conclusions: The use of diagnostics in the propensity score medical literature is far from optimal, with different diagnostics preferred in different areas of medicine. The propensity score literature may improve with focused efforts to change practice in areas where suboptimal practice is most common.
    • A systematic review of enteral feeding by nasogastric tube in young people with eating disorders

      Hindley, Kristen; orcid: 0000-0002-0001-5056; email: kristen.hindley@student.manchester.ac.uk; Fenton, Clare; McIntosh, Jennifer (BioMed Central, 2021-07-22)
      Abstract: Background: Adolescents with severe restrictive eating disorders often require enteral feeding to provide lifesaving treatment. Nasogastric feeding (NG) is a method of enteral nutrition often used in inpatient settings to treat medical instability, to supplement poor oral intake or to increase nutritional intake. This systematic review sets out to describe current practice of NG in young people with eating disorders. Methods: A systematic review following PRISMA guidelines was conducted by searching AMED, EMBASE and MEDLINE databases from 2000 to 2020. Inclusion terms were: enteral feeding by nasogastric tube, under 18 years, eating disorders, and primary research. Exclusion terms: psychiatric disorders other than eating disorders; non-primary research; no outcomes specific to NG feeding and participants over 18 years. Titles and abstracts were screened by all authors before reviewing full length articles. Quality assessment, including risk of bias, was conducted by all authors. Results: Twenty-nine studies met the full criteria. 86% of studies were deemed high or medium risk of bias due to the type of study: 34.4% retrospective cohort and 10.3% RCT; 17.2% were qualitative. Studies identified 1) a wide range of refeeding regimes depending on country, settings, and the reason for initiation; 2) standard practice is to introduce Nasogastric feeds (NG) if medically unstable or oral intake alone is inadequate; 3) NG may enable greater initial weight gain due to increased caloric intake; 4) there are 3 main types of feeding regime: continuous, nocturnal and bolus; 5) complications included nasal irritation, epistaxis, electrolyte disturbance, distress and tube removal; 6) where NG is routinely implemented to increase total calorie intake, length of stay in hospital may be reduced; however where NG is implemented in correlation to severity of symptoms, it may be increased; 7) both medical and psychiatric wards most commonly report using NG in addition to oral intake. Conclusions: NG feeding is a safe and efficacious method of increasing total calorie intake by either supplementing oral intake or continuously. There are currently no direct comparisons between continuous, nocturnal or bolus regimes, which may be used to direct future treatment for YP with ED.
    • Access to systemic anti-cancer therapies for women with secondary breast cancer—protocol for a mixed methods systematic review

      Pearson, Sally Anne; orcid: 0000-0002-7796-2617; email: sally.pearson@postgrad.manchester.ac.uk; Taylor, Sally; Marsden, Antonia; Yorke, Janelle (BioMed Central, 2021-07-23)
      Abstract: Background: It is well recognised that access and receipt of appropriate guideline recommended treatment with systemic anti-cancer therapies for secondary breast cancer is a key determinant in overall survival. Where there is disparity in access this may result in unwarranted variation and disparity in outcomes. Individual, clinical and wider contextual factors have been associated with these disparities, however this remains poorly understood for women with secondary breast cancer. The purpose of the review is to examine individual, clinical and contextual factors which influence access to evidence-based systemic anti-cancer therapies for women with secondary breast cancer. This will include barriers and facilitators for access and receipt of treatment and an exploration of women and clinicians experience and perspectives on access. Methods: A mixed methods approach with a segregated design will be used to examine and explore factors which influence access to systemic anti-cancer therapies for women with secondary breast cancer. Electronic databases to be searched from January 2000 onwards will be EBSCO CINAHL Plus, Ovid MEDLINE, Ovid EMBASE, PsychINFO and the Cochrane Library and JBI database. This will include NHS Evidence which will be searched for unpublished studies and gray literature. Title and abstract citations and full-text articles will be screened by the author and second reviewer. Data will be extracted by the author and validated by the second reviewer. An overarching synthesis will be produced which brings together quantitative and qualitative findings. Methodological quality and risk of bias will be assessed using the Mixed Methods Appraisal Tool. Discussion: Understanding individual, clinical and wider contextual factors associated with access and receipt of systemic anti-cancer therapies for secondary breast cancer is a complex phenomenon. These will be examined to determine any association with access. Review findings will be used to guide future research in this area and the development of an evidence-based service level intervention designed to address unwarranted variation in access based upon the Medical Research Council (MRC) approach to the development, implementation and evaluation of complex interventions. Systematic review registration: The review protocol has been registered in PROSPERO CRD42020196490.
    • Assessing the relation between alcohol consumption and risk of disease and mortality

      Alam, Benyamin; orcid: 0000-0002-6349-2650; email: benyamin.alam@student.manchester.ac.uk; Anwar, Mehreen; Bareli, Leonardo; Chowdhury, Shamia (BioMed Central, 2021-06-28)
    • 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.
    • Brief Engagement and Acceptance Coaching for Hospice Settings (the BEACHeS study): results from a Phase I study of acceptability and initial effectiveness in people with non-curative cancer

      Hulbert-Williams, Nicholas J.; email: n.hulbertwilliams@chester.ac.uk; Norwood, Sabrina F.; Gillanders, David; Finucane, Anne M.; Spiller, Juliet; Strachan, Jenny; Millington, Susan; Kreft, Joseph; Swash, Brooke (BioMed Central, 2021-06-25)
      Abstract: Objectives: Transitioning into palliative care is psychologically demanding for people with advanced cancer, and there is a need for acceptable and effective interventions to support this. We aimed to develop and pilot test a brief Acceptance and Commitment Therapy (ACT) based intervention to improve quality of life and distress. Methods: Our mixed-method design included: (i) quantitative effectiveness testing using Single Case Experimental Design (SCED), (ii) qualitative interviews with participants, and (iii) focus groups with hospice staff. The five-session, in-person intervention was delivered to 10 participants; five completed at least 80%. Results: At baseline, participants reported poor quality of life but low distress. Most experienced substantial physical health deterioration during the study. SCED analysis methods did not show conclusively significant effects, but there was some indication that outcome improvement followed changes in expected intervention processes variables. Quantitative and qualitative data together demonstrates acceptability, perceived effectiveness and safety of the intervention. Qualitative interviews and focus groups were also used to gain feedback on intervention content and to make design recommendations to maximise success of later feasibility trials. Conclusions: This study adds to the growing evidence base for ACT in people with advanced cancer. A number of potential intervention mechanisms, for example a distress-buffering hypothesis, are raised by our data and these should be addressed in future research using randomised controlled trial designs. Our methodological recommendations—including recruiting non-cancer diagnoses, and earlier in the treatment trajectory—likely apply more broadly to the delivery of psychological intervention in the palliative care setting. This study was pre-registered on the Open Science Framework (Ref: 46,033) and retrospectively registered on the ISRCTN registry (Ref: ISRCTN12084782).
    • Canine Genetics and Epidemiology is now Canine Medicine and Genetics

      Ollier, William; email: Bill.Ollier@manchester.ac.uk; Gaschen, Frédéric; email: fgaschen@lsu.edu; Kennedy, Lorna (BioMed Central, 2020-07-27)
    • Children and young people’s experiences of completing mental health and wellbeing measures for research: learning from two school-based pilot projects

      Demkowicz, Ola; orcid: 0000-0001-9204-0912; email: ola.demkowicz@manchester.ac.uk; Ashworth, Emma; Mansfield, Rosie; Stapley, Emily; Miles, Helena; Hayes, Daniel; Burrell, Kim; Moore, Anna; Deighton, Jessica (BioMed Central, 2020-09-16)
      Abstract: Background: In recent years there has been growing interest in child and adolescent mental health and wellbeing, alongside increasing emphasis on schools as a crucial site for research and intervention. This has coincided with an increased use of self-report mental health and wellbeing measures in research with this population, including in school-based research projects. We set out to explore the way that children and young people perceive and experience completing mental health and wellbeing measures, with a specific focus on completion in a school context, in order to inform future measure and research design. Methods: We conducted semi-structured interviews and focus groups with 133 participants aged 8–16 years following their completion of mental health and wellbeing measures as part of school-based research programmes, using thematic analysis to identify patterns of experience. Findings: We identified six themes: Reflecting on emotions during completion; the importance of anonymity; understanding what is going to happen; ease of responding to items; level of demand; and interacting with the measure format. Conclusions: Our findings offer greater insight into children and young people’s perceptions and experiences in reporting on their mental health and wellbeing. Such understanding can be used to support more ethical and robust data collection procedures in child and adolescent mental health research, both for data quality and ethical purposes. We offer several practical recommendations for researchers, including facilitating this in a school context.
    • Chronic anticoagulation is not associated with a reduced risk of acute kidney injury in hospitalised Covid-19 patients

      Parker, Kathrine; email: Kathrine.parker@postgrad.manchester.ac.uk; Hamilton, Patrick; Hanumapura, Prasanna; Castelino, Laveena; Murphy, Michelle; Challiner, Rachael; Thachil, Jecko; Ebah, Leonard (BioMed Central, 2021-06-16)
      Abstract: Background: Coronavirus-19 (COVID-19) has been declared a global pandemic by the World Health Organisation. Severe disease typically presents with respiratory failure but Acute Kidney Injury (AKI) and a hypercoagulable state can also occur. Early reports suggest that thrombosis may be linked with AKI. We studied the development of AKI and outcomes of patients with COVID-19 taking chronic anticoagulation therapy. Methods: Electronic records were reviewed for all adult patients admitted to Manchester University Foundation Trust Hospitals between March 10 and April 302,020 with a diagnosis of COVID-19. Patients with end-stage kidney disease were excluded. AKI was classified as per KDIGO criteria. Results: Of the 1032 patients with COVID-19 studied,164 (15.9%) were taking anticoagulant therapy prior to admission. There were similar rates of AKI between those on anticoagulants and those not anticoagulated (23.8% versus 19.7%) with no difference in the severity of AKI or requirement of renal replacement therapy between groups (1.2% versus 3.5%). Risk factors for AKI included hypertension, pre-existing renal disease and male sex. There was a higher mortality in those taking anticoagulant therapy (40.2% versus 30%). Patients taking anticoagulants were less likely to be admitted to the Intensive Care Unit (8.5% versus 17.4%) and to receive mechanical ventilation (42.9% versus 78.1%). Conclusion: Patients on chronic anticoagulant therapy did not have a reduced incidence or severity of AKI suggesting that AKI is unlikely to be thrombotic in nature. Therapeutic anticoagulation is currently still under investigation in randomised controlled studies to determine whether it has a potential role in COVID-19 treatment.
    • Clinical, humanistic, and economic burden of severe hemophilia B in the United States: Results from the CHESS US and CHESS US+ population surveys

      Burke, Tom; Asghar, Sohaib; orcid: 0000-0001-8276-0131; O’Hara, Jamie; Sawyer, Eileen K.; Li, Nanxin; email: n.li@uniqure.com (BioMed Central, 2021-03-20)
      Abstract: Background: Hemophilia B is a rare congenital bleeding disorder that has a significant negative impact on patients’ functionality and health-related quality of life. The standard of care for severe hemophilia B in the United States is prophylactic factor IX replacement therapy, which incurs substantial costs for this lifelong condition. Accurate estimates of the burden of hemophilia B are important for population health management and policy decisions, but have only recently accounted for current management strategies. The ‘Cost of Severe Hemophilia across the US: a Socioeconomic Survey’ (CHESS US) is a cross-sectional database of medical record abstractions and physician-reported information, completed by hematologists and care providers. CHESS US+ is a complementary database of completed questionnaires from patients with hemophilia. Together, CHESS US and CHESS US+ provide contemporary, comprehensive information on the burden of severe hemophilia from the provider and patient perspectives. We used the CHESS US and CHESS US+ data to analyze the clinical, humanistic, and economic burden of hemophilia B for patients treated with factor IX prophylaxis between 2017 and 2019 in the US. Results: We conducted analysis to assess clinical burden and direct medical costs from 44 patient records in CHESS US, and of direct non-medical costs, indirect costs, and humanistic burden (using the EQ-5D-5L) from 57 patients in CHESS US+. The mean annual bleed rate was 1.73 (standard deviation, 1.39); approximately 9% of patients experienced a bleed-related hospitalization during the 12-month study period. Nearly all patients (85%) reported chronic pain, and the mean EQ-5D-5L utility value was 0.76 (0.24). The mean annual direct medical cost was $614,886, driven by factor IX treatment (mean annual cost, $611,971). Subgroup analyses showed mean annual costs of $397,491 and $788,491 for standard and extended half-life factor IX treatment, respectively. The mean annual non-medical direct costs and indirect costs of hemophilia B were $2,371 and $6,931. Conclusions: This analysis of patient records and patient-reported outcomes from CHESS US and CHESS US+ provides updated information on the considerable clinical, humanistic, and economic burden of hemophilia B in the US. Substantial unmet needs remain to improve patient care with sustainable population health strategies.
    • Co-expression of C9orf72 related dipeptide-repeats over 1000 repeat units reveals age- and combination-specific phenotypic profiles in Drosophila

      West, Ryan J. H.; orcid: 0000-0001-9873-2258; email: r.j.west@sheffield.ac.uk; Sharpe, Joanne L.; Voelzmann, André; Munro, Anna L.; Hahn, Ines; Baines, Richard A.; Pickering-Brown, Stuart; email: SPB@Manchester.ac.uk (BioMed Central, 2020-09-07)
      Abstract: A large intronic hexanucleotide repeat expansion (GGGGCC) within the C9orf72 (C9orf72-SMCR8 Complex Subunit) locus is the most prevalent genetic cause of both Frontotemporal Dementia (FTD) and Motor Neuron Disease (MND). In patients this expansion is typically hundreds to thousands of repeat units in length. Repeat associated non-AUG translation of the expansion leads to the formation of toxic, pathological Dipeptide-Repeat Proteins (DPRs). To date there remains a lack of in vivo models expressing C9orf72 related DPRs with a repeat length of more than a few hundred repeats. As such our understanding of how physiologically relevant repeat length DPRs effect the nervous system in an ageing in vivo system remains limited. In this study we generated Drosophila models expressing DPRs over 1000 repeat units in length, a known pathological length in humans. Using these models, we demonstrate each DPR exhibits a unique, age-dependent, phenotypic and pathological profile. Furthermore, we show co-expression of specific DPR combinations leads to distinct, age-dependent, phenotypes not observed through expression of single DPRs. We propose these models represent a unique, in vivo, tool for dissecting the molecular mechanisms implicated in disease pathology, opening up new avenues in the study of both MND and FTD.
    • Comparison of the impact of two national health and social care integration programmes on emergency hospital admissions

      Morciano, Marcello; orcid: 0000-0002-0009-5201; email: marcello.morciano@manchester.ac.uk; Checkland, Katherine; orcid: 0000-0002-9961-5317; Durand, Mary Alison; orcid: 0000-0003-2205-4002; Sutton, Matt; orcid: 0000-0002-6635-2127; Mays, Nicholas; orcid: 0000-0001-9808-8466 (BioMed Central, 2021-07-12)
      Abstract: Background: Policy-makers expect that integration of health and social care will improve user and carer experience and reduce avoidable hospital use. We evaluate the impact on emergency hospital admissions of two large nationally-initiated service integration programmes in England: the Pioneer (November 2013 to March 2018) and Vanguard (January 2015 to March 2018) programmes. The latter had far greater financial and expert support from central agencies. Methods: Of the 206 Clinical Commissioning Groups (CCGs) in England, 51(25%) were involved in the Pioneer programme only, 22(11%) were involved in the Vanguard programme only and 13(6%) were involved in both programmes. We used quasi-experimental methods to compare monthly counts of emergency admissions between four groups of CCGs, before and after the introduction of the two programmes. Results: CCGs involved in the programmes had higher monthly hospital emergency admission rates than non-participants prior to their introduction [7.9 (95% CI:7.8–8.1) versus 7.5 (CI:7.4–7.6) per 1000 population]. From 2013 to 2018, there was a 12% (95% CI:9.5–13.6%) increase in emergency admissions in CCGs not involved in either programme while emergency admissions in CCGs in the Pioneer and Vanguard programmes increased by 6.4% (95% CI: 3.8–9.0%) and 8.8% (95% CI:4.5–13.1%), respectively. CCGs involved in both initiatives experienced a smaller increase of 3.5% (95% CI:-0.3–7.2%). The slowdown largely occurred in the final year of both programmes. Conclusions: Health and social care integration programmes can mitigate but not prevent rises in emergency admissions over the longer-term. Greater financial and expert support from national agencies and involvement in multiple integration initiatives can have cumulative effects.
    • Comparison of the impact of two national health and social care integration programmes on emergency hospital admissions

      Morciano, Marcello; orcid: 0000-0002-0009-5201; email: marcello.morciano@manchester.ac.uk; Checkland, Katherine; orcid: 0000-0002-9961-5317; Durand, Mary Alison; orcid: 0000-0003-2205-4002; Sutton, Matt; orcid: 0000-0002-6635-2127; Mays, Nicholas; orcid: 0000-0001-9808-8466 (BioMed Central, 2021-07-12)
      Abstract: Background: Policy-makers expect that integration of health and social care will improve user and carer experience and reduce avoidable hospital use. [We] evaluate the impact on emergency hospital admissions of two large nationally-initiated service integration programmes in England: the Pioneer (November 2013 to March 2018) and Vanguard (January 2015 to March 2018) programmes. The latter had far greater financial and expert support from central agencies. Methods: Of the 206 Clinical Commissioning Groups (CCGs) in England, 51(25%) were involved in the Pioneer programme only, 22(11%) were involved in the Vanguard programme only and 13(6%) were involved in both programmes. We used quasi-experimental methods to compare monthly counts of emergency admissions between four groups of CCGs, before and after the introduction of the two programmes. Results: CCGs involved in the programmes had higher monthly hospital emergency admission rates than non-participants prior to their introduction [7.9 (95% CI:7.8–8.1) versus 7.5 (CI: 7.4–7.6) per 1000 population]. From 2013 to 2018, there was a 12% (95% CI:9.5–13.6%) increase in emergency admissions in CCGs not involved in either programme while emergency admissions in CCGs in the Pioneer and Vanguard programmes increased by 6.4% (95% CI: 3.8–9.0%) and 8.8% (95% CI:4.5–13.1%), respectively. CCGs involved in both initiatives experienced a smaller increase of 3.5% (95% CI:-0.3–7.2%). The slowdown largely occurred in the final year of both programmes. Conclusions: Health and social care integration programmes can mitigate but not prevent rises in emergency admissions over the longer-term. Greater financial and expert support from national agencies and involvement in multiple integration initiatives can have cumulative effects.
    • Correction to: Factors determining ultra-short-term survival and the commencement of active treatment in high-grade serous ovarian cancer: a case comparison study

      Hawarden, Amy; Russell, Bryn; Gee, Mary Ellen; Kayali, Fatima; Clamp, Andrew; Crosbie, Emma Jayne; Edmondson, Richard John; email: richard.edmondson@manchester.ac.uk (BioMed Central, 2021-05-26)
    • Correction to: Quality of life improved for patients after starting dialysis but is impaired, initially, for their partners: a multi-centre, longitudinal study

      Moore, Currie; email: currie.moore@postgrad.manchester.ac.uk; Carter, Lesley-Anne; Mitra, Sandip; Skevington, Suzanne; Wearden, Alison (BioMed Central, 2020-07-06)
      An amendment to this paper has been published and can be accessed via the original article.
    • Correction to: The role of real-world data in the development of treatment guidelines: a case study on guideline developers’ opinions about using observational data on antibiotic prescribing in primary care

      Steels, Stephanie; email: Stephanie.Steels@manchester.ac.uk; Van der Zande, Marieke; van Staa, Tjeerd Pieter (BioMed Central, 2020-05-26)
      An amendment to this paper has been published and can be accessed via the original article.
    • Development and validation of a multivariable prediction model for infection-related complications in patients with common infections in UK primary care and the extent of risk-based prescribing of antibiotics

      Mistry, Chirag; Palin, Victoria; Li, Yan; Martin, Glen P.; Jenkins, David; Welfare, William; Ashcroft, Darren M.; van Staa, Tjeerd; email: tjeerd.vanstaa@manchester.ac.uk (BioMed Central, 2020-05-21)
      Abstract: Background: Antimicrobial resistance is driven by the overuse of antibiotics. This study aimed to develop and validate clinical prediction models for the risk of infection-related hospital admission with upper respiratory infection (URTI), lower respiratory infection (LRTI) and urinary tract infection (UTI). These models were used to investigate whether there is an association between the risk of an infection-related complication and the probability of receiving an antibiotic prescription. Methods: The study used electronic health record data from general practices contributing to the Clinical Practice Research Datalink (CPRD GOLD) and Welsh Secure Anonymised Information Linkage (SAIL), both linked to hospital records. Patients who visited their general practitioner with an incidental URTI, LRTI or UTI were included and followed for 30 days for hospitalisation due to infection-related complications. Predictors included age, gender, clinical and medication risk factors, ethnicity and socioeconomic status. Cox proportional hazards regression models were used with predicted risks independently validated in SAIL. Results: The derivation and validation cohorts included 8.1 and 2.7 million patients in CPRD and SAIL, respectively. A total of 7125 (0.09%) hospital admissions occurred in CPRD and 7685 (0.28%) in SAIL. Important predictors included age and measures of comorbidity. Initial attempts at validating in SAIL (i.e. transporting the models with no adjustment) indicated the need to recalibrate the models for age and underlying incidence of infections; internal bootstrap validation of these updated models yielded C-statistics of 0.63 (LRTI), 0.69 (URTI) and 0.73 (UTI) indicating good calibration. For all three infection types, the rate of antibiotic prescribing was not associated with patients’ risk of infection-related hospital admissions. Conclusion: The risk for infection-related hospital admissions varied substantially between patients, but prescribing of antibiotics in primary care was not associated with risk of hospitalisation due to infection-related complications. Our findings highlight the potential role of clinical prediction models to help inform decisions of prescribing of antibiotics in primary care.