• 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.
    • 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)
    • 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 haemophilia B in adults receiving factor IX prophylaxis: findings from the CHESS II real-world burden of illness study in Europe

      Burke, Tom; Asghar, Sohaib; O’Hara, Jamie; Chuang, Margaret; Sawyer, Eileen K.; Li, Nanxin; email: n.li@uniqure.com (BioMed Central, 2021-12-20)
      Abstract: Background: Real-world studies of the burden of severe haemophilia B in the context of recent therapeutic advances such as extended half-life (EHL) factor IX (FIX) products are limited. We analysed data from the recent CHESS II study to better understand the clinical, humanistic, and economic burden of severe haemophilia B in Europe. Data from male adults with severe haemophilia B receiving prophylaxis were analysed from the retrospective cross-sectional CHESS II study conducted in Germany, France, Italy, Spain and the United Kingdom. Inhibitors were exclusionary. Patients and physicians completed questionnaires on bleeding, joint status, quality of life, and haemophilia-related direct and indirect costs (2019–2020). All outcomes were summarised using descriptive statistics. Results: A total of 75 CHESS II patients were eligible and included; 40 patients (53%) provided self-reported outcomes. Mean age was 36.2 years. Approximately half the patients were receiving EHL versus standard half-life (SHL) prophylaxis (44% vs 56%). Most patients reported mild or moderate chronic pain (76%) and had ≥ 2 bleeding events per year (70%), with a mean annualised bleed rate of 2.4. Mean annual total haemophilia-related direct medical cost per patient was €235,723, driven by FIX costs (€232,328 overall, n = 40; €186,528 for SHL, €290,620 for EHL). Mean annual indirect costs (€8,973) were driven by early retirement or work stoppage due to haemophilia. Mean quality of life (EQ-5D) score was 0.67. Conclusions: These data document a substantial, persistent real-world burden of severe haemophilia B in Europe. Unmet needs persist for these patients, their caregivers, and society.
    • 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; 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.
    • 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 LUCID study: living with ulcerative colitis; identifying the socioeconomic burden in Europe

      Ruiz-Casas, Leonardo; Evans, Jonathan; orcid: 0000-0002-3490-7191; email: jonathan.evans@hcdeconomics.com; Rose, Alison; Pedra, Gabriel Ghizzi; Lobo, Alan; Finnegan, Alan; Hayee, Bu; Peyrin-Biroulet, Laurent; Sturm, Andreas; Burisch, Johan; et al. (BioMed Central, 2021-12-15)
    • 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.
    • Developing and implementing guidelines on culturally adapting the Addenbrooke’s cognitive examination version III (ACE-III): a qualitative illustration

      Waheed, Waquas; Mirza, Nadine; orcid: 0000-0002-1308-9046; email: nadine.mirza@postgrad.manchester.ac.uk; Waheed, Muhammed Wali; Malik, Abid; Panagioti, Maria (BioMed Central, 2020-10-06)
      Abstract: Background: Cognitive tests currently used in healthcare and research settings do not account for bias in performance that arises due to cultural context. At present there are no universally accepted steps or minimum criteria for culturally adapting cognitive tests. We propose a methodology for developing specific guidelines to culturally adapt a specific cognitive test and used this to develop guidelines for the ACE-III. We then demonstrated their implementation by using them to produce an ACE-III Urdu for a British South Asian population. Methods: This was a several stage qualitative study. We combined information from our systematic review on the translation and cultural adaptation of the ACE-III with feedback from previous ACE-III adaptors. This identified steps for cultural adaptation. We formatted these into question-by-question guidelines. These guidelines, along with feedback from focus groups with potential users were used to develop ACE-III Urdu questions. Clinical experts reviewed these questions to finalise an ACE-III Urdu. Results: Our systematic review found 32 adaptations and we received feedback from seven adaptors to develop the guidelines. With these guidelines and two focus groups with 12 participants a sample ACE-III Urdu was developed. A consensus meeting of two psychiatrists with a South Asian background and familiarity with cognitive tests and cultural adaptation finalised the ACE-III Urdu. Conclusions: We developed a set of guidelines for culturally adapting the ACE-III that can be used by future adaptors for their own language or cultural context. We demonstrated how guidelines on cultural adaptation can be developed for any cognitive test and how they can be used to adapt it.
    • 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 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.