• 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 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)
    • Association of apolipoprotein E gene polymorphisms with blood lipids and their interaction with dietary factors

      Shatwan, Israa M.; Winther, Kristian H.; Ellahi, Basma; Elwood, Peter; Ben-Shlomo, Yoav; Givens, Ian; Rayman, Margaret P.; Lovegrove, Julie A.; Vimaleswaran, Karani S.; University of Reading; King Abdulaziz University; University Hospital Denmark; University of Chester; University Hospital of Wales; University of Bristol; University of Surrey (BioMed Central, 2018-04-30)
      Background: Several candidate genes have been identified in relation to lipid metabolism, and among these, lipoprotein lipase (LPL) and apolipoprotein E (APOE) gene polymorphisms are major sources of genetically determined variation in lipid concentrations. This study investigated the association of two single nucleotide polymorphisms (SNPs) at LPL, seven tagging SNPs at the APOE gene, and a common APOE haplotype (two SNPs) with blood lipids, and examined the interaction of these SNPs with dietary factors. Methods: The population studied for this investigation included 660 individuals from the Prevention of Cancer by Intervention with Selenium (PRECISE) study who supplied baseline data. The findings of the PRECISE study were further replicated using 1238 individuals from the Caerphilly Prospective cohort (CaPS). Dietary intake was assessed using a validated food-frequency questionnaire (FFQ) in PRECISE and a validated semi-quantitative FFQ in the CaPS. Interaction analyses were performed by including the interaction term in the linear regression model adjusted for age, body mass index, sex and country. Results: There was no association between dietary factors and blood lipids after Bonferroni correction and adjustment for confounding factors in either cohort. In the PRECISE study, after correction for multiple testing, there was a statistically significant association of the APOE haplotype (rs7412 and rs429358; E2, E3, and E4) and APOE tagSNP rs445925 with total cholesterol (P = 4 × 10− 4 and P = 0.003, respectively). Carriers of the E2 allele had lower total cholesterol concentration (5.54 ± 0.97 mmol/L) than those with the E3 (5.98 ± 1.05 mmol/L) (P = 0.001) and E4 (6.09 ± 1.06 mmol/L) (P = 2 × 10− 4) alleles. The association of APOE haplotype (E2, E3, and E4) and APOE SNP rs445925 with total cholesterol (P = 2 × 10− 6 and P = 3 × 10− 4, respectively) was further replicated in the CaPS. Additionally, significant association was found between APOE haplotype and APOE SNP rs445925 with low density lipoprotein cholesterol in CaPS (P = 4 × 10− 4 and P = 0.001, respectively). After Bonferroni correction, none of the cohorts showed a statistically significant SNP-diet interaction on lipid outcomes. Conclusion: In summary, our findings from the two cohorts confirm that genetic variations at the APOE locus influence plasma total cholesterol concentrations, however, the gene-diet interactions on lipids require further investigation in larger cohorts.
    • Autologous chondrocyte implantation-derived synovial fluids display distinct responder and non-responder proteomic profiles

      Hulme, Charlotte H.; Wilson, Emma L.; Peffers, Mandy J.; Roberts, Sally; Simpson, Deborah M.; Richardson, James B.; Gallacher, Pete; Wright, Karina T.; Keele University; Robert Jones and Agnes Hunt Orthopaedic Hospital; University of Chester; University of Liverpool (BioMed Central, 2017-06-30)
      Background Autologous chondrocyte implantation (ACI) can be used in the treatment of focal cartilage injuries to prevent the onset of osteoarthritis (OA). However, we are yet to understand fully why some individuals do not respond well to this intervention. Identification of a reliable and accurate biomarker panel that can predict which patients are likely to respond well to ACI is needed in order to assign the patient to the most appropriate therapy. This study aimed to compare the baseline and mid-treatment proteomic profiles of synovial fluids (SFs) obtained from responders and non-responders to ACI. Methods SFs were derived from 14 ACI responders (mean Lysholm improvement of 33 (17–54)) and 13 non-responders (mean Lysholm decrease of 14 (4–46)) at the two stages of surgery (cartilage harvest and chondrocyte implantation). Label-free proteome profiling of dynamically compressed SFs was used to identify predictive markers of ACI success or failure and to investigate the biological pathways involved in the clinical response to ACI. Results Only 1 protein displayed a ≥2.0-fold differential abundance in the preclinical SF of ACI responders versus non-responders. However, there is a marked difference between these two groups with regard to their proteome shift in response to cartilage harvest, with 24 and 92 proteins showing ≥2.0-fold differential abundance between Stages I and II in responders and non-responders, respectively. Proteomic data has been uploaded to ProteomeXchange (identifier: PXD005220). We have validated two biologically relevant protein changes associated with this response, demonstrating that matrix metalloproteinase 1 was prominently elevated and S100 calcium binding protein A13 was reduced in response to cartilage harvest in non-responders. Conclusions The differential proteomic response to cartilage harvest noted in responders versus non-responders is completely novel. Our analyses suggest several pathways which appear to be altered in non-responders that are worthy of further investigation to elucidate the mechanisms of ACI failure. These protein changes highlight many putative biomarkers that may have potential for prediction of ACI treatment success.
    • 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)
    • 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.
    • 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.
    • The cost of severe haemophilia in Europe: the CHESS study

      O’Hara, Jamie; Hughes, David; Camp, Charlotte; Burke, Tom; Carroll, Liz; Diego, Daniel-Anibal G.; University of Chester; HCD Economics, Daresbury; The Haeomophelia Society, London; FedHemo, Madrid (BioMed Central, 2017-05-31)
      Background Severe haemophilia is associated with major psychological and economic burden for patients, caregivers, and the wider health care system. This burden has been quantified and documented for a number of European countries in recent years. However, few studies have taken a standardised methodology across multiple countries simultaneously, and sought to amalgamate all three levels of burden for severe disease. The overall aim of the ‘Cost of Haemophilia in Europe: a Socioeconomic Survey’ (CHESS) study was to capture the annualised economic and psychosocial burden of severe haemophilia in five European countries. A cross-section of haemophilia specialists (surveyed between January and April 2015) provided demographic and clinical information and 12-month ambulatory and secondary care activity for patients via an online survey. In turn, patients provided corresponding direct and indirect non-medical cost information, including work loss and out-of-pocket expenses, as well as information on quality of life and adherence. The direct and indirect costs for the patient sample were calculated and extrapolated to population level. Results Clinical reports for a total of 1,285 patients were received. Five hundred and fifty-two patients (43% of the sample) provided information on indirect costs and health-related quality of life via the PSC. The total annual cost of severe haemophilia across the five countries for 2014 was estimated at EUR 1.4 billion, or just under EUR 200,000 per patient. The highest per-patient costs were in Germany (mean EUR 319,024) and the lowest were in the United Kingdom (mean EUR 129,365), with a study average of EUR 199,541. As expected, consumption of clotting factor replacement therapy represented the vast majority of costs (up to 99%). Indirect costs are driven by patient and caregiver work loss. Conclusions The results of the CHESS study reflect previous research findings suggesting that costs of factor replacement therapy account for the vast majority of the cost burden in severe haemophilia. However, the importance of the indirect impact of haemophilia on the patient and family should not be overlooked. The CHESS study highlights the benefits of observational study methodologies in capturing a ‘snapshot’ of information for patients with rare diseases.
    • Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

      Eccles, Suzanne A.; Aboagye, Eric O.; Ali, Simak; Anderson, Annie S.; Armes, Jo; Berditchevski, Fedor; Blaydes, Jeremy P.; Brennan, Keith; Brown, Nicola J.; Bryant, Helen E.; et al. (BioMed Central, 2013-10-01)
      Introduction: Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice. Methods More than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer ‘stem’ cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account. Results The 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working. Conclusions With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years.
    • Development and feasibility of a Swallowing intervention Package (SiP) for patients receiving radiotherapy treatment for head and neck cancer—the SiP study protocol

      Wells, Mary; King, Emma; Toft, Kate; MacAulay, Fiona; Patterson, Joanne; Dougall, Nadine; Hulbert-Williams, Nicholas J.; Boa, Sally; Slaven, Eleanor; Cowie, Julie; et al. (BioMed Central, 2016-08-04)
      Background Head and neck cancer (HNC) is the sixth most common cancer worldwide, and the functional, psychological and social consequences of HNC cancer and its treatment can be severe and chronic. Dysphagia (swallowing problems) affects up to two thirds of patients undergoing combined chemoradiotherapy. Recent reviews suggest that prophylactic swallowing exercises may improve a range of short- and long-term outcomes; however, the importance of psychological and behavioural factors on adherence to swallowing exercises has not been adequately studied. This study aims to develop and test the feasibility of a Swallowing intervention Package (SiP) designed in partnership with patients, speech and language therapists (SLTs) and other members of the head and neck multi-disciplinary team (MDT), for patients undergoing chemoradiotherapy (CRT) or radiotherapy (RT) for head and neck cancer. Methods/design This feasibility study uses quantitative and qualitative research methods, within a quasi-experimental design, to assess whether patients will tolerate and adhere to the SiP intervention, which aspects of the intervention can be implemented and which cannot, whether treatment fidelity can be achieved across different contexts, whether study processes and outcome measures will be feasible and acceptable and to what extent the intervention is likely to have an impact on swallowing dysfunction and quality of life. Patients are being recruited from five sites in Scotland and England (three interventions and two usual care). The SLT based in the relevant intervention centre teaches the exercise programme and provides supporting materials. A combination of patient-reported outcome measures (PROMs), adherence measures and clinical swallowing assessments are used prior to intervention (baseline), at the end of treatment, 3 and 6 months post-treatment. Discussion This collaborative study has taken a unique approach to the development of a patient-centred and evidence-based swallowing intervention. The introduction of an e-SiP app provides an exploration of the use of technology in delivering this intervention. The study provides an opportunity to examine the feasibility of delivering and participating in a supported swallowing intervention across several different NHS sites and will provide the evidence needed to refine intervention and study processes for a future trial. Trial registration NCRI portfolio, 18192 & 20259
    • 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.
    • Development of mental healthcare in Cambodia: barriers and opportunities

      Parry, Sarah J.; orcid: 0000-0002-9730-3547; email: sarah.parry11@nhs.net; Ean, Nil; Sinclair, Shirley P.; Wilkinson, Ewan; orcid: 0000-0002-2167-8756 (BioMed Central, 2020-07-29)
      Abstract: Background: Despite the increasing recognition globally of the importance of mental health for sustainable development, significant barriers remain to developing mental health services in low- and middle-income countries. This study explored the particular barriers and opportunities for developing mental health services in Cambodia and how these compared with those described in other low- and middle-income countries. Methods: For this qualitative study, 18 experienced mental health professionals from different disciplines were selected using purposive sampling. Semi-structured interviews were carried out in Phnom Penh and thematic analysis of the data was completed. Results: Five key themes were identified: (1) Prioritising mental health in Cambodia, (2) Strengthening collaborations between mental health stakeholders, (3) Developing a mental healthcare model appropriate for the Cambodian culture and context, (4) Increasing the quantity and (5) Improving the quality of mental healthcare. All five themes were referred to by all 18 participants and the two most repeated themes were (2) Strengthening collaborations and (5) Improving the quality of mental healthcare. Conclusions: The themes identified in this study both corroborate previous barriers identified to developing mental health services in low- and middle-income countries and shed new light on opportunities of particular importance in Cambodia. Strengthening collaborations between key stakeholders in mental health and prioritising the quality of mental health education, training and service provision were both cited as being significant opportunities for enhancing the development of mental health services in Cambodia. These have not been widely described before as being important factors.