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ABSTRACT Group A Streptococcus (GAS) necrotizing fasciitis (NF) is a difficult-to-treat bacterial infection associated with high morbidity and mortality despite extensive surgery and targeted antibiotic treatment. Difficult-to-treat infections are often characterized by the presence of bacteria surviving prolonged antibiotic exposure without displaying genetic resistance, referred to as persisters. In the present study, we investigated the presence of GAS persisters in tissue freshly debrided from patients as well as in an in vivo mouse model of NF and examined the phenomenon of antibiotic tolerance. Time-lapse imaging of GAS plated directly upon isolation from NF debrided tissue and an antibiotic challenge-based persisters assay were used to assess the presence of persisters. We show for the first time that GAS recovered directly from freshly debrided NF tissue is characterized by heterogeneous and overall delayed colony appearance time, suggesting the presence of persisters. Acidic pH or nutrient stress exposure, mimicking the NF-like environment in vitro, led to a similar phenotypic heterogeneity and resulted in enhanced survival upon antibiotic challenge, confirming the presence of GAS persisters. GAS persisters might contribute to NF treatment failure, despite extensive surgery and adequate antibiotic treatment.IMPORTANCEDifficult-to-treat and recurrent infections are a global problem burdening society and the health care system alike. Unraveling the mechanisms by which bacteria can survive antibiotic treatment without developing genetic resistance is of utmost importance to lay the foundation for new, effective therapeutic approaches. For the first time, we describe the phenomenon of antibiotic tolerance in group A Streptococcus (GAS) isolated from necrotizing fasciitis (NF) patients. Dormant, non-replicating cells (persisters) are tolerant to antibiotics and their occurrence in vivo is reported in an increasing number of bacterial species. Tailored treatment options, including the use of persisters-targeting drugs, need to be developed to specifically target dormant bacteria causing difficult-to-treat and recurrent infections.

BackgroundIn order for low and middle income countries (LMIC) to transition to Human Papilloma Virus (HPV) test based cervical cancer screening, a greater understanding of how to implement these evidence based interventions (EBI) among vulnerable populations is needed. This paper documents outcomes of an implementation research on HPV screening among women from tribal, rural, urban slum settings in India.MethodsA mixed-method, pragmatic, quasi-experimental trial design was used. HPV screening on self-collected cervical samples was offered to women aged 30-60 years. Implementation strategies were 1) Assessment of contextual factors using both qualitative and quantitative methods like key informant interviews (KII), focus group discussions (FGDs), pre-post population sample surveys, capacity assessment of participating departments 2) enhancing provider capacity through training workshops, access to HPV testing facility, colposcopy, thermal ablation/cryotherapy at the primary health care centers 3) community engagement, counselling for self-sampling and triage process by frontline health care workers (HCWs). Outcomes were assessed using the RE-AIM (Reach, Effectiveness, adoption, implementation, maintenance) framework.ResultsScreening rate in 8 months' of study was 31.0%, 26.7%, 32.9%, prevalence of oncogenic HPV was 12.1%, 3.1%, 5.5%, compliance to triage was 53.6%, 45.5%, 84.6% in tribal, urban slum, rural sites respectively. Pre-cancer among triage compliant HPV positive women was 13.6% in tribal, 4% in rural and 0% among urban slum women. Unique challenges faced in the tribal setting led to programme adaptations like increasing honoraria of community health workers for late-evening work and recalling HPV positive women for colposcopy by nurses, thermal ablation by gynaecologist at the outreach camp site.ConclusionsSelf-collection of samples combined with HCW led community engagement activities, flexible triage processes and strengthening of health system showed an acceptable screening rate and better compliance to triage, highlighting the importance of identifying the barriers and developing strategies suitable for the setting.Trial registrationCTRI/2021/09/036130.

Objectives To engage children who have experienced cancer, childhood cancer survivors, their families and professionals to systematically identify and prioritise research questions about childhood cancer to inform the future research agenda.Design James Lind Alliance Priority Setting Partnership.Setting UK health service and community.Methods A steering group oversaw the initiative. Potential research questions were collected in an online survey, then checked to ensure they were unanswered. Shortlisting via a second online survey identified the highest priority questions. A parallel process with children was undertaken. A final consensus workshop was held to determine the Top 10 priorities.Participants Children and survivors of childhood cancer, diagnosed before age 16, their families, friends and professionals who work with this population.Results Four hundred and eighty-eight people submitted 1299 potential questions. These were refined into 108 unique questions; 4 were already answered and 3 were under active study, therefore, removed. Three hundred and twenty-seven respondents completed the shortlisting survey. Seventy-one children submitted questions in the children’s surveys, eight children attended a workshop to prioritise these questions. The Top 5 questions from children were taken to the final workshop where 23 questions in total were discussed by 25 participants (young adults, carers and professionals). The top priority was ‘can we find effective and kinder (less burdensome, more tolerable, with fewer short and long-term effects) treatments for children with cancer, including relapsed cancer?’Conclusions We have identified research priorities for children’s cancer from the perspectives of children, survivors, their families and the professionals who care for them. Questions reflect the breadth of the cancer experience, including diagnosis, relapse, hospital experience, support during/after treatment and the long-term impact of cancer. These should inform funding of future research as they are the questions that matter most to the people who could benefit from research.

Abstract Background Urogenital cancers are common, accounting for approximately 20% of cancer incidence globally. Cancers belonging to the same organ system often present with similar symptoms, making initial management challenging. In this study, 511 cases of cancer were recorded after the date of consultation among 61,802 randomly selected patients presenting in primary care in six European countries: a subgroup analysis of urogenital cancers was carried out in order to study variation in symptom presentation. Methods Initial data capture was by completion of standardised forms containing closed questions about symptoms recorded during the consultation. The general practitioner (GP) provided follow-up data after diagnosis, based on medical record data made after the consultation. GPs also provided free text comments about the diagnostic procedure for individual patients. Results The most common symptoms were mainly associated with one or two specific types of cancer: ‘Macroscopic haematuria’ with bladder or renal cancer (combined sensitivity 28.3%), ‘Increased urinary frequency’ with bladder (sensitivity 13.3%) or prostatic (sensitivity 32.1%) cancer, or to uterine body (sensitivity 14.3%) cancer, ‘Unexpected genital bleeding’ with uterine cancer (cervix, sensitivity 20.0%, uterine body, sensitivity 71.4%). ‘Distended abdomen, bloating’ had sensitivity 62.5% (based on eight cases of ovarian cancer). In ovarian cancer, increased abdominal circumference and a palpable tumour also were important diagnostic elements. Specificity for ‘Macroscopic haematuria’ was 99.8% (99.7–99.8). PPV > 3% was noted for ‘Macroscopic haematuria’ and bladder or renal cancer combined, for bladder cancer in male patients. In males aged 55–74, PPV = 7.1% for ‘Macroscopic haematuria’ and bladder cancer. Abdominal pain was an infrequent symptom in urogenital cancers. Conclusions Most types of urogenital cancer present with rather specific symptoms. If the GP considers ovarian cancer, increased abdominal circumference should be actively determined. Several cases were clarified through the GP’s clinical examination, or laboratory investigations.

Abstract Background Targeted lung cancer screening is effective in reducing mortality by upwards of twenty percent. However, screening is not universally available and uptake is variable and socially patterned. Understanding screening behaviour is integral to designing a service that serves its population and promotes equitable uptake. We sought to review the literature to identify barriers and facilitators to screening to inform the development of a pilot lung screening study in Scotland. Methods We used Arksey and O’Malley’s scoping review methodology and PRISMA-ScR framework to identify relevant literature to meet the study aims. Qualitative, quantitative and mixed methods primary studies published between January 2000 and May 2021 were identified and reviewed by two reviewers for inclusion, using a list of search terms developed by the study team and adapted for chosen databases. Results Twenty-one articles met the final inclusion criteria. Articles were published between 2003 and 2021 and came from high income countries. Following data extraction and synthesis, findings were organised into four categories: Awareness of lung screening, Enthusiasm for lung screening, Barriers to lung screening, and Facilitators or ways of promoting uptake of lung screening. Awareness of lung screening was low while enthusiasm was high. Barriers to screening included fear of a cancer diagnosis, low perceived risk of lung cancer as well as practical barriers of cost, travel and time off work. Being health conscious, provider endorsement and seeking reassurance were all identified as facilitators of screening participation. Conclusions Understanding patient reported barriers and facilitators to lung screening can help inform the implementation of future lung screening pilots and national lung screening programmes.

Abstract Introduction Targeted lung cancer screening is effective in reducing lung cancer and all‐cause mortality according to major trials in the United Kingdom and Europe. However, the best ways of implementing screening in local communities requires an understanding of the population the programme will serve. We undertook a study to explore the views of those potentially eligible for, and to identify potential barriers and facilitators to taking part in, lung screening, to inform the development of a feasibility study. Methods Men and women aged 45–70, living in urban and rural Scotland, and either self‐reported people who smoke or who recently quit, were invited to take part in the study via research agency Taylor McKenzie. Eleven men and 14 women took part in three virtual focus groups exploring their views on lung screening. Focus group transcripts were transcribed and analysed using thematic analysis, assisted by QSR NVivo. Findings Three overarching themes were identified: (1) Knowledge, awareness and acceptability of lung screening, (2) Barriers and facilitators to screening and (3) Promoting screening and implementation ideas. Participants were largely supportive of lung screening in principle and described the importance of the early detection of cancer. Emotional and psychological concerns as well as system‐level and practical issues were discussed as posing barriers and facilitators to lung screening. Conclusions Understanding the views of people potentially eligible for a lung health check can usefully inform the development of a further study to test the feasibility and acceptability of lung screening in Scotland. Patient or Public Contribution The LUNGSCOT study has convened a patient advisory group to advise on all aspects of study development and implementation. Patient representatives commented on the focus group study design, study materials and ethics application, and two representatives read the focus group transcripts.

Abstract Background Health behaviour can change outcomes in both healthy and unhealthy populations and are particularly useful in promoting compliance to treatment and maintaining fidelity to care seeking and follow-up options in chronic diseases. Interventions to change health behaviour based on psychological theory are more often successful than those without any underlying theory. The theory of planned behaviour (TPB) is one such psychological theory which had been found to predict human behaviour with respect to disease prevention and when applied to interventions can change the outcomes of diseases. Most of the research evidence of TPB-based interventions have been from developed world. Evidence is required whether TPB-based interventions can be applied and works in low-resource, low health-literacy settings of low- and middle-income countries (LMICs). Methods The protocol has been developed as per PRISMA-P guidelines and incorporates PICO (population, intervention, comparison, outcomes) framework for describing the methodology. Population above 18 years of age and having any chronic disease (as defined for this systematic review) will be selected, while any health or educational intervention based on constructs of TPB will be included. Comparison will be with non-TPB-based interventions or treatment as usual without any intervention, and the primary outcome will be the behaviour change effected by the TPB-based intervention. Intervention studies will be considered, and relevant databases like MEDLINE, Embase, Cochrane Library and ProQuest will be explored. Data extraction will done in a standardised form, and risk-of-bias assessment will be done using the Cochrane Collaboration’s tools for such assessment. Narrative synthesis of the selected studies will be done to draw the conclusions, and meta-analysis will be done to calculate the effect estimates with I-squared statistics to describe the heterogeneity. Discussion This systematic review will provide new evidence on fidelity and effectiveness of the TPB-based interventions among chronic disease patients from low health literacy, resource-poor background. It will inform of how to plan and use such interventions to change health behaviour in chronic disease patients, particularly in LMIC settings. Systematic review registration PROSPERO CRD42018104890 .

The Covid-19 pandemic has significantly disrupted all aspects of healthcare, and while the worst may be over, its broader impact on health services, such as cancer diagnosis and treatment, is likely to be profound. We examine, in this paper, how our response to Covid-19 impacted on the recognition, referral, and diagnosis of individuals with lung cancer in primary care. The overlapping nature of symptoms of Covid-19 and lung cancer posed a particular challenge, and lung cancer referrals have been slow to return to pre-pandemic levels. Strategies need to be implemented to ensure the impact of future variants does not derail the precarious recovery we are now witnessing in many countries—it is vital that the gains we have made in earlier diagnosis are not lost. The pandemic has underlined the importance of improving early diagnosis through public awareness raising of symptoms, rapid diagnostic facilities, reduced primary care diagnostic intervals and, potentially, the introduction of screening in high-risk groups.

Abstract Background Patients with brain tumours often present with non-specific symptoms. Correctly identifying who to prioritise for urgent brain imaging is challenging. Brain tumours are amongst the commonest cancers diagnosed as an emergency presentation. A verbal fluency task (VFT) is a rapid triage test affected by disorders of executive function, language and processing speed. We tested whether a VFT could support identification of patients with a brain tumour. Methods This proof-of-concept study examined whether a VFT can help differentiate patients with a brain tumour from those with similar symptoms (i.e. headache) without a brain tumour. Two patient populations were recruited, (a) patients with known brain tumour, and (b) patients with headache referred for Direct-Access Computed-Tomography (DACT) from primary care with a suspicion of a brain tumour. Semantic and phonemic verbal fluency data were collected prospectively. Results 180 brain tumour patients and 90 DACT patients were recruited. Semantic verbal fluency score was significantly worse for patients with a brain tumour than those without (P < 0.001), whether comparing patients with headache, or patients without headache. Phonemic fluency showed a similar but weaker difference. Raw and incidence-weighted positive and negative predictive values were calculated. Conclusion We have demonstrated the potential role of adding semantic VFT score performance into clinical decision making to support triage of patients for urgent brain imaging. A relatively small improvement in the true positive rate in patients referred for DACT has the potential to increase the timeliness and efficiency of diagnosis and improve patient outcomes.

Abstract Respiratory diseases remain a significant cause of global morbidity and mortality and primary care plays a central role in their prevention, diagnosis and management. An e-Delphi process was employed to identify and prioritise the current respiratory research needs of primary care health professionals worldwide. One hundred and twelve community-based physicians, nurses and other healthcare professionals from 27 high-, middle- and low-income countries suggested 608 initial research questions, reduced after evidence review by 27 academic experts to 176 questions covering diagnosis, management, monitoring, self-management and prognosis of asthma, COPD and other respiratory conditions (including infections, lung cancer, tobacco control, sleep apnoea). Forty-nine questions reached 80% consensus for importance. Cross-cutting themes identified were: a need for more effective training of primary care clinicians; evidence and guidelines specifically relevant to primary care, adaption for local and low-resource settings; empowerment of patients to improve self-management; and the role of the multidisciplinary healthcare team.

Abstract Background New Zealand has high rates of colorectal cancer (CRC) but poor outcomes. Most patients with CRC are diagnosed following referral from general practice, where a general practitioner (GP) assesses symptoms according to national guidelines. All referred patients are then re-prioritised by the hospital system. The first objective of this study was to identify what proportion of patients referred by general practice to surgical/gastroenterology at Waikato District Health Board (DHB) had a colonoscopy. The second objective was to determine what proportion of these referrals have an underlying CRC and the factors associated with the likelihood of this diagnosis. Methods This study is a retrospective analysis of e-referral data for patients aged 30–70+ who were referred from 75 general practices to general surgery, gastroenterology or direct to colonoscopy at Waikato DHB, 01 January 2015–31 December 2017. Primary and secondary outcome measures included the proportion and characteristics of patients who were having colonoscopy, and of those, who were diagnosed with CRC. Data were analysed using chi square and logistic regression. Results 6718/20648 (32.5%) patients had a colonoscopy and 372 (5.5%) of these were diagnosed with CRC. The probability of having CRC following a colonoscopy increased with age (p value

Objectives A growing body of evidence suggests longer time between symptom onset and start of treatment affects breast cancer prognosis. To explore this association, the International Cancer Benchmarking Partnership Module 4 examined differences in breast cancer diagnostic pathways in 10 jurisdictions across Australia, Canada, Denmark, Norway, Sweden and the UK.Setting Primary care in 10 jurisdictions.Participant Data were collated from 3471 women aged >40 diagnosed for the first time with breast cancer and surveyed between 2013 and 2015. Data were supplemented by feedback from their primary care physicians (PCPs), cancer treatment specialists and available registry data.Primary and secondary outcome measures Patient, primary care, diagnostic and treatment intervals.Results Overall, 56% of women reported symptoms to primary care, with 66% first noticing lumps or breast changes. PCPs reported 77% presented with symptoms, of whom 81% were urgently referred with suspicion of cancer (ranging from 62% to 92%; Norway and Victoria). Ranges for median patient, primary care and diagnostic intervals (days) for symptomatic patients were 3–29 (Denmark and Sweden), 0–20 (seven jurisdictions and Ontario) and 8–29 (Denmark and Wales). Ranges for median treatment and total intervals (days) for all patients were 15–39 (Norway, Victoria and Manitoba) and 4–78 days (Sweden, Victoria and Ontario). The 10% longest waits ranged between 101 and 209 days (Sweden and Ontario).Conclusions Large international differences in breast cancer diagnostic pathways exist, suggesting some jurisdictions develop more effective strategies to optimise pathways and reduce time intervals. Targeted awareness interventions could also facilitate more timely diagnosis of breast cancer.

Abstract Background The introduction of screening in the UK and other high‐income countries led to a significant decrease in the incidence of cervical cancer and increase in survival rates. Minority ethnic groups are often underrepresented in screening participation for reasons that are poorly understood. Objective To explore experiences of cervical screening participation and non‐participation of women from minority ethnic populations in Scotland and gain insights to support the development of interventions that could potentially support screening participation and thereby reduce inequalities. Design Qualitative comparison group study using in‐depth, semi‐structured individual interviews that were thematically analysed. Setting and participants This study took place in Scotland. Fifty women were purposively sampled from four ethnic minority groups: South Asian; East European; Chinese; and Black African or Caribbean. White Scottish women were also interviewed. Results Many experiences described were common regardless of ethnicity, such as difficulties managing competing priorities, including work and care responsibilities. However, important differences existed across the groups. These included going abroad for more frequent screening, delayed introduction to screening and not accessing primary care services, language difficulties in health‐care settings despite proficiency in English and not being sexually active at screening commencement. Experiences of racism, ignorance and feeling shamed were also reported. Conclusions Key differences exist in the experience of minority ethnic groups in Scotland. These offer potential opportunities to reduce disparity and support screening participation including maximizing co‐incidental interactions and developing outreach work.

Abstract Background In an abdominal symptom study in primary care in six European countries, 511 cases of cancer were recorded prospectively among 61,802 patients 16 years and older in Norway, Denmark, Sweden, Netherlands, Belgium and Scotland. Colorectal cancer is one of the main types of cancer associated with abdominal symptoms; hence, an in-depth subgroup analysis of the 94 colorectal cancers was carried out in order to study variation in symptom presentation among cancers in different anatomical locations. Method Initial data capture was by completion of standardised forms containing closed questions about symptoms recorded during the consultation. Follow-up data were provided by the GP after diagnosis, based on medical record data made after the consultation. GPs also provided free text comments about the diagnostic procedure for individual patients. Fisher’s exact test was used to analyse differences between groups. Results Almost all symptoms recorded could indicate colorectal cancer. ‘Rectal bleeding’ had a specificity of 99.4% and a PPV of 4.0%. Faecal occult blood in stool (FOBT) or anaemia may indicate gastrointestinal bleeding: when these symptoms and signs were combined, sensitivity reached 57.5%, with 69.2% for cancer in the distal colon. For proximal colon cancers, none of 18 patients had ‘Rectal bleeding’ at the initial consultation, but three of the 18 did so at a later consultation. ‘Abdominal pain, lower part’, ‘Constipation’ and ‘Distended abdomen, bloating’ were less specific and also less sensitive than ‘Rectal bleeding’, and with PPV between 0.7% and 1.9%. Conclusions Apart from rectal bleeding, single symptoms did not reach the PPV 3% NICE threshold. However, supplementary information such as a positive FOBT or persistent symptoms may revise the PPV upwards. If a colorectal cancer is suspected by the GP despite few symptoms, the total clinical picture may still reach the NICE PPV threshold of 3% and justify a specific referral.

Abstract Background More people are surviving a first primary cancer and experiencing a second, different cancer. However, little is known about the diagnostic journeys of patients with second primary cancer (SPC). This study explores the views of patients and general practitioners (GPs) on their experiences of pathways to diagnosis of SPC, including the influence of a previous diagnosis of cancer on symptom appraisal, help-seeking and referral decisions. Methods Qualitative interviews with patients with a SPC diagnosis and case-linked GP interviews in a Scottish primary care setting. In-depth face to face or telephone interviews were conducted, underpinned by a social constructionist approach. Interviews were transcribed and Braun and Clarke’s thematic analysis undertaken. Three analysts from the research team read transcripts and developed the coding framework using QSR NVivo version 10, with input from a fourth researcher. Themes were developed from refined codes and interpreted in the context of existing literature and theory. Results Interviews were conducted with 23 patients (aged 43–84 years) with a SPC diagnosis, and 7 GPs. Five patient themes were identified: Awareness of SPC, symptom appraisal and help-seeking, pathways to diagnosis, navigating the healthcare system, and impact of SPC. GPs interviews identified: experience and knowledge of SPC and referrals and decision-making. Conclusions Insights into the pathway to diagnosis of SPC highlights the need for increased awareness of and vigilance for SPC among patients and healthcare providers (HCPs), and emotional support to manage the psychosocial burden.

Abstract Background New Zealand (NZ) has a high incidence of colorectal cancer (CRC) and low rates of early diagnosis. With screening not yet nationwide, the majority of CRC is diagnosed through general practice. A good patient-general practitioner (GP) relationship can facilitate prompt diagnosis, but when there is a breakdown in this relationship, delays can occur. Delayed diagnosis of CRC in NZ receives a disproportionally high number of complaints directed against GPs, suggesting deficits in the patient-GP connection. We aimed to investigate patient-reported confidence and ratings of their GP following the diagnostic process. Methods This study is a mixed methods analysis of responses to a structured questionnaire and free text comments from patients newly diagnosed with CRC in the Midland region of NZ. A total of 195 patients responded to the structured questionnaire, and 113 patients provided additional free text comments. Descriptive statistics were used to describe the study population and chi square analysis determined the statistical significance of factors possibly linked to delay. Free text comments were analysed using a thematic framework. Results Most participants rated their GP as ‘Very good/Good’ at communication with patients about their health conditions and involving them in decisions about their care, and 6.7% of participants rated their overall level of confidence and trust in their GP as ‘Not at all’. Age, gender, ethnicity and a longer diagnostic interval were associated with lower confidence and trust. Free text comments were grouped in to three themes: 1. GP Interpersonal skills; (communication, listening, taking patient symptoms seriously), 2. Technical competence; (speed of referral, misdiagnoses, lack of physical examination), and 3. Organisation of general practice care; (appointment length, getting an appointment, continuity of care). Conclusions Māori, females, and younger participants were more likely to report low confidence and trust in their GP. Participants associate a poor diagnostic experience with deficits in the interpersonal and technical skills of their GP, and health system factors within general practice. Short appointment times, access to appointments and poor GP continuity are important components of how patients assess their experience and are particularly important to ensure equal access for Māori patients.

ABSTRACT INTRODUCTIONOver 3000 cases of colorectal cancer (CRC) are diagnosed annually in New Zealand. The proportion of late stage diagnoses is higher than in similar countries, and highest in Māori and Pacific patients. Survival outcomes are poorer than for people in Australia and poor for Māori and Pacific peoples. A regional screening programme is not yet available to the entire target population (60–74 years). AIMThis study reviews research investigating the pre-diagnostic pathway for CRC in New Zealand and how this may contribute to poorer outcomes. METHODSThis was a scoping review of original articles examining the pre-diagnostic period for CRC published on the PubMed database between 2009 and 2019. Findings were interpreted within the Model of Pathways to Treatment framework and in context of international evidence. RESULTSIn total, 83 publications were assessed; eight studies were included. Studies were mainly older than 5 years, qualitative, and focused on screening. Facilitatory factors for the appraisal and help-seeking intervals increased CRC public awareness and the critical role of general practitioners. No specific facilitatory or inhibitory factors were identified for the diagnostic interval, but two studies found that time frames did not meet national and international targets. One study discovered longer pre-diagnostic intervals were associated with younger age at diagnosis. DISCUSSIONLimited recent research has investigated the CRC pre-diagnostic pathways in NZ. Identification of facilitatory and inhibitory factors and implementation of appropriate strategies to improve them alongside the wider uptake of the screening programme may improve stage at diagnosis and outcomes for New Zealand CRC patients.

Abstract Background New Zealand (NZ) has high rates of colorectal cancer but low rates of early diagnosis. Due to a lack of understanding of the pre-diagnostic experience from the patient’s perspective, it is necessary to investigate potential patient and health system factors that contribute to longer diagnostic intervals. Previous qualitative studies have discussed delays using The Model of Pathways to Treatment, but this has not been explored in the NZ context. This study aimed to understand the patient experience and perception of their general practitioner (GP) through the diagnostic process in the Waikato region of NZ. In particular, we sought to investigate potential barriers and facilitators that contribute to longer diagnostic intervals. Methods Ethical approval for this study was granted by the New Zealand Health and Disability Ethics Committee. Twenty-eight participants, diagnosed with colorectal cancer, were interviewed about their experience. Semi-structured interviews were audio recorded, transcribed verbatim and analysed thematically using The Model of Pathways to Treatment framework (intervals: appraisal, help-seeking, diagnostic). Results Participant appraisal of symptoms was a barrier to prompt diagnosis, particularly if symptoms were normalised, intermittent, or isolated in occurrence. Successful self-management techniques also resulted in delayed help-seeking. However if symptoms worsened, disruption to work and daily routines were important facilitators to seeking a GP consultation. Participants positively appraised GPs if they showed good technical competence and were proactive in investigating symptoms. Negative GP appraisals were associated with a lack of physical examinations and misdiagnosis, and left participants feeling dehumanised during the diagnostic process. However high levels of GP interpersonal competence could override poor technical competence, resulting in an overall positive experience, even if the cancer was diagnosed at an advanced stage. Māori participants often appraised symptoms inclusive of their sociocultural environment and considered the impact of their symptoms in relation to family. Conclusions The findings of this study highlight the importance of tailored colorectal cancer symptom communication in health campaigns, and indicate the significance of the interpersonal competence aspect of GP-patient interactions. These findings suggest that interpersonal competence be overtly displayed in all GP interactions to ensure a higher likelihood of a positive experience for the patient.

Introduction The aim of the study was to develop and validate a clinical prediction rule (CPR) for foot ulceration in people with diabetes.Research design and methods Development of a CPR using individual participant data from four international cohort studies identified by systematic review, with validation in a fifth study. Development cohorts were from primary and secondary care foot clinics in Europe and the USA (n=8255, adults over 18 years old, with diabetes, ulcer free at recruitment). Using data from monofilament testing, presence/absence of pulses, and participant history of previous ulcer and/or amputation, we developed a simple CPR to predict who will develop a foot ulcer within 2 years of initial assessment and validated it in a fifth study (n=3324). The CPR’s performance was assessed with C-statistics, calibration slopes, calibration-in-the-large, and a net benefit analysis.Results CPR scores of 0, 1, 2, 3, and 4 had a risk of ulcer within 2 years of 2.4% (95% CI 1.5% to 3.9%), 6.0% (95% CI 3.5% to 9.5%), 14.0% (95% CI 8.5% to 21.3%), 29.2% (95% CI 19.2% to 41.0%), and 51.1% (95% CI 37.9% to 64.1%), respectively. In the validation dataset, calibration-in-the-large was −0.374 (95% CI −0.561 to −0.187) and calibration slope 1.139 (95% CI 0.994 to 1.283). The C-statistic was 0.829 (95% CI 0.790 to 0.868). The net benefit analysis suggested that people with a CPR score of 1 or more (risk of ulceration 6.0% or more) should be referred for treatment.Conclusion The clinical prediction rule is simple, using routinely obtained data, and could help prevent foot ulcers by redirecting care to patients with scores of 1 or above. It has been validated in a community setting, and requires further validation in secondary care settings.

# Background The burden of multimorbidity is rising globally. In sub-Saharan Africa (SSA), the growing prevalence of non-communicable diseases alongside the already existing high burden of chronic communicable diseases such as human immunodeficiency virus (HIV) presents a complex form of multimorbidity relative to patterns observed in high income countries. There is a gap in understanding the true burden of multimorbidity in SSA, in particular at interface of chronic communicable and non-communicable diseases (NCDs). The primary objective of this systematic review is to identify, evaluate and summarise the evidence on the prevalence and patterns of chronic communicable and NCDs multimorbidity in SSA. # Methods and analysis This protocol was developed in compliance with the Preferred Reporting Items for Systematic Review and Meta-Analyses Protocols (PRISMA-P) guidelines. A comprehensive search will be conducted on selected electronic databases including Medline, Embase, African Journals Online, based on a predefined search strategy for observational studies reporting primary data on multimorbidity from any country in the SSA region. Additionally, we will explore grey literature databases and check reference lists of included studies. Study selection, assessment of quality of included studies and data extraction will be carried out independently by two reviewers. A narrative synthesis will be conducted and meta-analysis will be carried out where applicable. # Conclusion The proposed systematic review will provide insights into the interface of chronic communicable diseases and NCDs in SSA. We expect this will provide additional insights into the true picture of multimorbidity in the region and assist policy makers to design appropriate prevention and management strategies. This review does not require ethical approval. Upon completion, it will be submitted for publication in peer-reviewed journals, and disseminated through relevant academic conferences. **Prospero registration**: CRD42020183539

# Background Poor cervical cancer screening coverage and utilization by women in low- and middle-income countries (LMICs) are linked to health system factors such as lack of access and availability of quality health care, inadequate workforce capacity, and socio-cultural and behavioral barriers. To improve women’s participation in cervical screening, strategies such as involvement of community resources have been recommended. The aim of this review is to understand the current roles of community-based resources (CBRs) such as community health workers (CHWs) and community-based civil society organizations (CBOs) including key stakeholders – for example health champions, traditional leaders, chief’s wives, etc. in the community in cervical screening in LMICs settings. # Methods and analysis We will conduct a scoping review of MEDLINE, CINAHL and Global Health databases from January 2016 to June 2020 for published peer-reviewed literature from LMICs including reference list tracking and handsearching of studies with community focus published in English describing interventions provided by CBRs in cervical screening uptake. # Ethics and dissemination Ethical approval is not required. Findings from this review will be summarised for conferences and published in peer-reviewed journals for widespread dissemination. Study will identify possible gaps in the evidence and differences in the role of CBRs between sub-Saharan Africa (SSA) and other LMIC regions and inform recommendations and implementation of future cervical screening research, policy, and practice.

BackgroundChronic respiratory diseases (CRDs) are major causes of mortality and morbidity worldwide with a substantial burden of the disease being borne by the low and middle income countries (LMICs). Interventions to change health behaviour which aim to improve the quality of life and reduce disease burden due to CRD require knowledge of the problem and factors influencing such behaviour. Our study sought to appreciate the lived experiences of people with CRD, their understanding of the disease and its risk factors, and usual practice of health behaviour in a rural low-literate community in southern India.MethodsQualitative data were collected between September and December 2018 through eight focus group discussions (FGDs), five in-depth interviews and four key-informant interviews from patients and community members. Community engagement was undertaken prior to the study and all interviews and discussions were recorded with permission. Inductive coding was used to thematically analyse the results.ResultsMajor themes included understanding of chronic lung disease, health behaviours, lived experiences with the disease and social norms, attitudes and other factors influencing health behaviour.DiscussionPoor understanding of CRDs and their risk factors affect health seeking behaviour and/or health practices. Stigma associated with the disease and related health behaviours (e.g. inhaler use) creates emotional challenges and mental health problems, besides influencing health behaviour. However barriers can be circumvented by increasing community awareness; communication and connection with the community through community based health care providers can turn challenges into opportunities for better health care.

Background: Diabetes-related foot ulcers give rise to considerable morbidity, generate a high monetary cost for health and social care services and precede the majority of diabetes-related lower extremity amputations. There are many clinical prediction rules in existence to assess risk of foot ulceration but few have been subject to validation. Objectives: Our objectives were to produce an evidence-based clinical pathway for risk assessment and management of the foot in people with diabetes mellitus to estimate cost-effective monitoring intervals and to perform cost-effectiveness analyses and a value-of-information analysis. Design: We developed and validated a prognostic model using predictive modelling, calibration and discrimination techniques. An overview of systematic reviews already completed was followed by a review of randomised controlled trials of interventions to prevent foot ulceration in diabetes mellitus. A review of the health economic literature was followed by the construction of an economic model, an analysis of the transitional probability of moving from one foot risk state to another, an assessment of cost-effectiveness and a value-of-information analysis. Interventions: The effects of simple and complex interventions and different monitoring intervals for the clinical prediction rules were evaluated. Main outcome measure: The main outcome was the incidence of foot ulceration. We compared the new clinical prediction rules in conjunction with the most effective preventative interventions at different monitoring intervals with a ‘treat-all’ strategy. Data sources: Data from an electronic health record for 26,154 people with diabetes mellitus in one Scottish health board were used to estimate the monitoring interval. The Prediction Of Diabetic foot UlcerationS (PODUS) data set was used to develop and validate the clinical prediction rule. Review methods: We searched for eligible randomised controlled trials of interventions using search strategies created for Ovid® (Wolters Kluwer, Alphen aan den Rijn, the Netherlands), MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials. Randomised controlled trials in progress were identified via the International Standard Randomised Controlled Trial Number Registry and systematic reviews were identified via PROSPERO. Databases were searched from inception to February 2019. Results: The clinical prediction rule was found to accurately assess the risk of foot ulceration. Digital infrared thermometry, complex interventions and therapeutic footwear with offloading devices were found to be effective in preventing foot ulcers. The risk of developing a foot ulcer did not change over time for most people. We found that interventions to prevent foot ulceration may be cost-effective but there is uncertainty about this. Digital infrared thermometry and therapeutic footwear with offloading devices may be cost-effective when used to treat all people with diabetes mellitus regardless of their ulcer risk. Limitations: The threats to the validity of the results in some randomised controlled trials in the review and the large number of missing data in the electronic health record mean that there is uncertainty in our estimates. Conclusions: There is evidence that interventions to prevent foot ulceration are effective but it is not clear who would benefit most from receiving the interventions. The ulceration risk does not change over an 8-year period for most people with diabetes mellitus. A change in the monitoring interval from annually to every 2 years for those at low risk would be acceptable. Future work recommendations: Improving the completeness of electronic health records and sharing data would help improve our knowledge about the most clinically effective and cost-effective approaches to prevent foot ulceration in diabetes mellitus. Study registration: This study is registered as PROSPERO CRD42016052324. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 62. See the NIHR Journals Library website for further project information.

Abstract Background Over recent years there has been a growth in cancer early diagnosis (ED) research, which requires valid measurement of routes to diagnosis and diagnostic intervals. The Aarhus Statement, published in 2012, provided methodological guidance to generate valid data on these key pre-diagnostic measures. However, there is still a wide variety of measuring instruments of varying quality in published research. In this paper we test comprehension of self-completion ED questionnaire items, based on Aarhus Statement guidance, and seek input from patients, GPs and ED researchers to refine these questions. Methods We used personal interviews and consensus approaches to generate draft ED questionnaire items, then a combination of focus groups and telephone interviews to test comprehension and obtain feedback. A framework analysis approach was used, to identify themes and potential refinements to the items. Results We found that many of the questionnaire items still prompted uncertainty in respondents, in both routes to diagnosis and diagnostic interval measurement. Uncertainty was greatest in the context of multiple or vague symptoms, and potentially ambiguous time-points (such as ‘date of referral’). Conclusions There are limits on the validity of self-completion questionnaire responses, and refinements to the wording of questions may not be able to completely overcome these limitations. It’s important that ED researchers use the best identifiable measuring instruments, but accommodate inevitable uncertainty in the interpretation of their results. Every effort should be made to increase clarity of questions and responses, and use of two or more data sources should be considered.

Abstract Background Bowel cancer is the third most common cause of cancer death worldwide. Bowel screening has been shown to reduce mortality and primary care interventions have been successful in increasing uptake of screening. Using evidence-based theory to inform the development of such interventions has been shown to increase their effectiveness. This study aimed to develop and refine a brief evidence-based intervention for eligible individuals whom have not responded to their last bowel screening invitation (non-responders), for opportunistic use by primary care providers during routine consultations. Methods The development of a brief intervention involving a conversation between primary care providers and non-responders was informed by a multi-faceted model comprising: research team workshop and meetings to draw on expertise; evidence from the literature regarding barriers to bowel screening and effective strategies to promote informed participation; relevant psychological theory, and intervention development and behaviour change guidance. Qualitative telephone interviews with 1) bowel screening stakeholders and 2) patient non-responders explored views regarding the acceptability of the intervention to help refine its content and process. Results The intervention provides a theory and evidence-based tool designed to be incorporated within current primary care practice. Bowel screening stakeholders were supportive of the intervention and recognised the importance of the role of primary care. Interviews highlighted the importance of brevity and simplicity to incorporate the intervention into routine clinical care. Non-responders similarly found the intervention acceptable, valuing a holistic approach to their care. Moreover, they expected their primary care provider to encourage participation. Conclusions A theory-based brief conversation for use in a primary care consultation was acceptable to bowel screening stakeholders and potential recipients, reflecting a health promoting primary care ethos. Findings indicate that it is appropriate to test the intervention in primary care in a feasibility study.

# Background Sub-Saharan Africa (SSA) accounts for about 70% of the global burden of cervical cancer; this is due to several factors including lack of access to cervical cancer screening, low knowledge of cervical cancer and screening services, poor-functioning health systems, insufficient and poorly trained health workers, and the high burden of human immunodefiency virus (HIV) infection. To date, to the best of our knowledge, there has been no systematic review of the literature on the role of community-based resources such as community health workers and community-based organisations in increasing the uptake and or continuing participation of women in cervical cancer screening, in the setting of high HIV burden, in sub-Saharan Africa. # Methods We will systematically search selected databases and websites from 1980 to date for published and grey literature including citation and reference list tracking, on studies with a community focus carried out in sub-Saharan Africa, without language restrictions. Randomised controlled trials (RCTs), observational studies, and qualitative and mixed methods studies of interventions (carried out with and without comparison groups) reporting impact on participation in cervical cancer screening in sub-Saharan Africa will be identified and assessed for methodological quality by two independent reviewers. We will use narrative synthesis and/or meta-analysis depending on the study selection. # Results Findings will be summarised into abstracts for presentation at conferences and submission to peer-reviewed journals in the field for wide-ranging dissemination to patients, researchers, healthcare professionals and policy makers on cervical cancer in sub-Saharan Africa. # Conclusion The review will address the gap in evidence for effective and implementable community-based strategies that encourages uptake of cervical cancer screening among women living in sub-Saharan Africa. The findings will have the potential to inform future screening practice and research with the hope of reducing the burden of cervical cancer in the region. # PROSPERO registration number -- CRD42018102539.

Cognitive impairment is as an important feature of Multiple Sclerosis (MS), and might be even more relevant to patients than mobility restrictions. Compared to the multitude of studies investigating memory deficits or basic cognitive slowing, executive dysfunction is a rarely studied cognitive domain in MS, and its neural correlates remain largely unexplored. Even rarer are topological studies on specific cognitive functions in MS. Here we used several structural MRI parameters – including cortical thinning and T2 lesion load – to investigate neural correlates of executive dysfunction, both on a global and a regional level by means of voxel- and vertex-wise analyses. Forty-eight patients with relapsing-remitting MS and 48 healthy controls participated in the study. Five executive functions were assessed, i.e. verbal and figural fluency, working memory, interference control and set shifting. Patients scored lower than controls in verbal and figural fluency only, and displayed widespread cortical thinning. On a global level, cortical thickness independently predicted verbal fluency performance, when controlling for lesion volume and central brain atrophy estimates. On a regional level, cortical thinning in the anterior cingulate region correlated with deficits in verbal and figural fluency and did so in a lateralised manner: Left-sided thinning was related to reduced verbal – but not figural – fluency, whereas the opposite pattern was observed for right-sided thinning. We conclude that executive dysfunction in MS patients can specifically affect verbal and figural fluency. The observed lateralised clinico-anatomical correlation has previously been described in brain-damaged patients with large focal lesions only, for example after stroke. Based on focal grey matter atrophy, we here show for the first time comparable lateralised findings in a white matter disease with widespread pathology.

Introduction Population-based screening has been shown to reduce cancer specific mortality. Within Scotland, three national screening programmes exist: breast, cervical and bowel. Despite being a common and preventable form of cancer, the uptake for bowel cancer screening among women lags behind that for breast and cervical cancer. Objectives and Approach Since the benefits of screening accrue with participation, it is important to understand why differences in screening uptake exist. In this study, data on women aged 24-74 in the Greater Glasgow and Clyde Health Board, invited to take part in one or more screening programme during the period 2009-2013, were linked to demographic and medical data. Uptake was determined based on the presence of a screening attendance or result; the impact of age, deprivation and co-morbidity on uptake was determined using logistic regression for each individual programme, and for the cohort of women invited to participate in all three programmes. Results Overall, 430,591 women were invited to take part in one or more screening programme during the study period. The uptake for bowel screening was, at 61.7%, lower than that seen in either the breast (72.6%) or cervical (80.7%) programme. Despite these differences, the same demographic factors were associated with uptake of each individual screening programme: older women and those living in affluent areas were most likely to attend. Medical factors did differentially influence uptake, those with multi-morbid illness being less likely to participate in breast and bowel, but not the cervical programme. For the 68,324 women invited to participate in all programmes, 52.1% took part in all three while 7.2% participated in none. Conclusion/Implications Uptake of bowel screening was confirmed as lower than uptake of other programmes, although all were similarly impacted by demographic, clinical and socioeconomic factors. Individuals were more likely to complete bowel screening if they participate in another programme, suggesting these may serve as a vehicle for improving bowel screening uptake.

Background: Abdominal symptoms are diagnostically challenging to general practitioners (GPs): although common, they may indicate cancer. In a prospective cohort of patients, we examined abdominal symptom frequency, initial diagnostic suspicion, and actions of GPs in response to abdominal symptoms. Methods: Over a 10-day period, 493 GPs in Norway, Denmark, Sweden, Belgium, the Netherlands, and Scotland, recorded consecutive consultations: sex, date of birth and any specified abdominal symptoms. For patients with abdominal symptoms, additional data on non-specific symptoms, GPs’ diagnostic suspicion, and features of the consultation were noted. Data on all cancer diagnoses among all included patients were requested from the GPs eight months later. Findings: Consultations with 61802 patients were recorded. Abdominal symptoms were recorded in 6264 (10.1%) patients. A subsequent malignancy was reported in 511 patients (0.8%): 441 (86.3%) had a new cancer, 70 (13.7%) a recurrent cancer. Abdominal symptoms were noted in 129 (25.2%) of cancer patients (P < 0.001), rising to 34.5% for the 89 patients with cancer located in the abdominal region. PPV for any cancer given any abdominal symptom was 2.1%.In symptomatic patients diagnosed with cancer, GPs noted a suspicion of cancer for 85 (65.9%) versus 1895 (30.9%) when there was no subsequent cancer (P < 0.001). No suspicion was noted in 32 (24.8%) cancer patients. The GP’s intuitive cancer suspicion was independently associated with a subsequent new cancer diagnosis (OR 2.11, 95% CI 1.15–3.89).Laboratory tests were ordered for 45.4% of symptomatic patients, imaging for 10.4%, referral or hospitalization for 20.0%: all were more frequent in subsequent cancer patients (P < 0.001). Interpretation: Abdominal symptoms pointed to abdominal cancers rather than to other cancers. However, the finding of abdominal symptoms in only one third of patients with an abdominal cancer, and the lack of cancer suspicion in a quarter of symptomatic cancer patients, provide challenges for GPs’ diagnostic thinking and referral practices.

Background: Lung cancer kills more people than any other cancer in the UK (5-year survival