Authors’ own creation
Type | Definition |
---|---|
Cities | Towns/settlements with populations greater than 50,000 |
Satellite urban towns | Towns/settlements with populations between 1,500 and 49,999, where 20% or more of the usually resident used population’s workplace address is in “Cities” |
Independent urban towns | Towns/settlements with populations between 1,500 and 49,999, where less than 20% of the usually resident employed population’s workplace address is in “Cities” |
Rural areas with high urban influence | Rural areas (themselves defined as having an area type with a population less than 1,500 persons, as per census 2016) are allocated to one of three sub-categories, based on their dependence on urban areas Again, employment location is the defining variable. The allocation is based on a weighted percentage of resident used adults of a rural small area who work in the three standard categories of urban area (for simplicity the methodology uses main, secondary and minor urban area). The percentages working in each urban area were weighted through the use of multipliers. The multipliers allowed for the increasing urbanisation for different sized urban areas. For example, the percentage of rural people working in a main urban area had double the impact of the same percentage working in a minor urban area. The weighting acknowledges the impact that a large urban centre has on its surrounding area The adopted weights for: Main urban areas is 2 Satellite urban communities is 1.5 Independent urban communities is 1 The weighted percentages is divided into tertials to assign one of the three rural breakdowns |
Rural areas with moderate urban influence | |
Highly rural/remote areas |
Area/Typology | Social enterprises | Population | Ratio (SE/10,000 inhabitants) | |||
---|---|---|---|---|---|---|
% | % | |||||
Highly rural/remote areas | 865 | 20.4 | 412,457 | 8.8 | 21.0 | 10.8 (total rural) |
Rural areas with moderate urban influence | 580 | 13.7 | 587,041 | 12.5 | 9.9 | |
Rural areas with high urban influence | 447 | 10.6 | 754,794 | 16.1 | 5.9 | |
Independent urban towns | 991 | 23.4 | 770,329 | 16.4 | 12.9 | 8.0 (total urban) |
Satellite urban towns | 293 | 6.9 | 597,355 | 12.8 | 4.9 | |
Cities | 1,058 | 25.0 | 1,567,945 | 33.4 | 6.7 | |
Total | 4,234 | 100 | 4,689,921 | 100 | 9.0 |
Authors’ own creation
Type of area | Childcare (%) | Community infrastructure and local development (%) | Health, youth services and social care (%) | Heritage, festivals, arts and creative industry (%) | Sport and leisure (%) | Training and work integration (%) | Information, support and financial services (%) | Housing (%) | Food, agriculture, catering (%) | Environment, circular economy and renewable energy (%) | Retailing (%) | Transport (%) | Manufacturing (%) | Other (%) |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Highly rural/remote areas | 28.7 | 23.8 | 8.6 | 15.7 | 5.3 | 3.5 | 3.6 | 2.9 | 3.1 | 2.3 | 1.4 | 0.2 | 0.2 | 0.6 |
Rural areas with moderate urban influence | 32.2 | 21.9 | 9.0 | 10.5 | 9.5 | 3.6 | 2.4 | 2.2 | 3.1 | 2.4 | 1.2 | 0.9 | 0.2 | 0.9 |
Rural areas with high urban influence | 23.7 | 22.4 | 9.4 | 10.1 | 13.4 | 4.7 | 5.6 | 3.4 | 3.6 | 2.2 | 0.4 | 0.0 | 0.2 | 1.1 |
Independent urban towns | 23.8 | 14.6 | 14.5 | 12.7 | 8.9 | 5.8 | 7.1 | 5.2 | 2.2 | 1.3 | 1.8 | 0.7 | 0.4 | 1.1 |
Satellite urban towns | 23.5 | 16.4 | 20.1 | 8.5 | 7.5 | 6.1 | 4.1 | 4.4 | 1.4 | 2.4 | 2.7 | 1.7 | 0.3 | 0.7 |
Cities | 28.9 | 7.9 | 18.9 | 5.6 | 4.3 | 9.5 | 9.8 | 7.0 | 2.2 | 4.0 | 0.6 | 0.2 | 0.4 | 0.7 |
All Ireland | 26.7 | 16.4 | 13.7 | 10.7 | 7.6 | 6.1 | 5.8 | 4.5 | 2.7 | 2.6 | 1.2 | 0.5 | 0.3 | 0.9 |
Authors’ own creation
Hypothesis | Decision |
---|---|
: the presence of social enterprises is significantly associated with the type of rural–urban areas | Supported |
: the presence of social enterprises is positively associated to areas with lower population density and greater distance to services and amenities (remoteness). | Supported |
: the presence of social enterprises within the capital city (Dublin) is significantly higher compared to the national average and to other rural and urban areas of Ireland | Not supported |
: there is a significant relationship between the sectors of activities in which social enterprises operate and the type of rural–urban areas in which they are based | Supported |
: there is a positive association between areas with lower population density and greater distance to services and amenities (remoteness) and the presence of social enterprises in community and local development | Supported |
: there is a negative association between areas with lower population density and greater distance to services and amenities (remoteness) and the presence of social enterprises operating in sectors related to welfare objectives such as childcare, health and social care | Not supported |
Authors’ own creation
df | -value | Decision | ||
---|---|---|---|---|
SEs ratio – rural/urban area | 309.17 | 5 | 2.2e ** | Supported |
Authors’ own creation
Comparison (pairwise) | Z | P. unadj | P. adj (Bonferroni) |
---|---|---|---|
Highly rural/remote areas – Rural areas with moderate urban influence | 6.432 | 1.26E-10 | 1.89E-09** |
Highly rural/remote areas – Rural areas with high urban influence | 9.694 | 3.21E-22 | 4.81E-21** |
Highly rural/remote areas – Independent urban towns | 3.866 | 0.000111 | 0.0017** |
Highly rural/remote areas – Satellite urban towns | 12.304 | 8.65E-35 | 1.308E-33** |
Highly rural/remote areas – Cities | −14.341 | 1.21E-46 | 1.81E-45** |
Rural areas with moderate urban influence – Rural areas with high urban influence | −3.256 | 0.001129 | 0.0169* |
Rural areas with moderate urban influence – Independent urban towns | 3.007 | 0.002637 | 0.0396* |
Rural areas with moderate urban influence – Satellite urban towns | 6.11 | 9.98E-10 | 1.50E-08** |
Rural areas with moderate urban influence – Cities | −6.657 | 2.79E-11 | 4.19E-10** |
Rural areas with high urban influence – Independent urban towns | 6.491 | 8.55E-11 | 1.28E-09** |
Rural areas with high urban influence – Satellite urban towns | 2.979 | 0.002889 | 0.0433* |
Rural areas with high urban influence – Cities | −2.772 | 0.005563 | 0.0834 |
Independent urban towns – Satellite urban towns | 9.378 | 6.74E-21 | 1.01E-19** |
Cities – Independent urban towns | −11.05 | 2.19E-28 | 3.28E-27** |
Cities – Satellite urban towns | 0.879 | 0.379665 | 1 |
Authors’ own creation
Alternative hypothesis | JT | -value | Decision | |
---|---|---|---|---|
Positive association area remoteness and ratio social enterprises | Increasing | 73161607 | 0.001** | Supported |
Authors’ own creation
t-test (Welch Two Sample t-test) | |||||
---|---|---|---|---|---|
Pairs (categories) compared | df | ci (95%) | Decision | ||
Dublin City – satellite urban towns | 1.6129 | 5,163.3 | 0.1068 | (−0.22, 2.24) | Not supported |
Dublin City – rural areas with high urban influence | 1.1337 | 6,491.1 | 0.2569 | (−0.46, 1.75) | Not supported |
Authors’ own creation
df | -value | Decision | ||
---|---|---|---|---|
Association between sector of activity SEs and rural–urban typology | 445.99 | 70 | 2.2e ** | Supported |
Authors’ own creation
and | Alternative hypothesis | JT | -value | Decision |
---|---|---|---|---|
: Positive association rural–urban remoteness and ratio social enterprises in community local development | Increasing | 13 | 0.02778* | Supported |
Negative association rural–urban remoteness and ratio social enterprises in welfare services | Decreasing | 3 | 0.06806 | Not supported |
* p < 0.05
Source: Authors’ own creation
The main source for selecting the papers for the literature review was a search on Scopus (conducted in early 2023), with the search string: TITLE-ABSTRACT-KEYWORDS (“geography” OR “rural” OR “urban” OR “regional”) AND “social enterprises”. From this search only papers where geography was considered an explanatory factor/dimension in the analysis of the features and/or work of social enterprises were selected. The article Douglas et al. (2018) was added by the authors.
Nomenclature of territorial units for statistics (see Eurostat, https://ec.europa.eu/eurostat/web/nuts/background )
The classification of regions into one of the three categories is based on the following criteria:
Population density. A community is defined as rural if its population density is below 150 inhabitants per km 2 (500 inhabitants for Japan to account for the fact that its national population density exceeds 300 inhabitants per km 2 ).
Regions by % population in rural communities. A region is classified as predominantly rural if more than 50% of its population lives in rural communities, predominantly urban if less than 15% of the population lives in rural communities, and intermediate if the share of the population living in rural communities is between 15% and 50%.
Urban centres. A region that would be classified as rural on the basis of the general rule is classified as intermediate if it has an urban centre of more than 200,000 inhabitants (500,000 for Japan) representing no less than 25% of the regional population. A region that would be classified as intermediate on the basis of the general rule is classified as predominantly urban if it has an urban centre of more than 500,000 inhabitants (1,000,000 for Japan) representing no less than 25% of the regional population.
More information about this methodology is available at: “Social Enterprises in Ireland – a Baseline data collection exercise” www.gov.ie/ga/foilsiuchan/b30e5-social-enterprises-in-ireland-a-baseline-data-collection-exercise/#:∼:text=In%202022%2C%20the%20Department%20of%20Rural%20and%20Community,sector%2C%20an%20online%20survey%20was%20developed%20and%20published
QGIS (Quantum Geographical Information System) is a free and open-source software for spatial analysis. See https://qgis.org/en/site/
Now Tailte Éireann, see https://data-osi.opendata.arcgis.com/
The more recent data for population at small area level at the time of this study was from Census 2016.
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This study have been funded by the Department of Rural and Community Development, Government of Ireland – NUI Post-Doctoral Fellowship in Rural Development 2022. The authors would like to thank you the funders for their support and three anonymous reviewers and the editors of the journal for their feedback.
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BMC Public Health volume 24 , Article number: 2427 ( 2024 ) Cite this article
Metrics details
Direct acting antivirals (DAAs) for the Hepatitis C virus (HCV) have shifted the World Health Organisation global strategic focus to the elimination of HCV by 2030. In England, the UK Health Security Agency (UKHSA) led a national ‘patient re-engagement exercise’, using routine surveillance data, which was delivered through the HCV Operational Delivery Networks (ODNs) with support from National Health Service England (NHSE), to help find and support people with a positive HCV PCR test result to access treatment. We report a quantitative evaluation of outcomes of this exercise.
Individuals with a recorded positive HCV antibody or PCR result between 1996 and 2017 were identified using UKHSA’s records of HCV laboratory diagnosis. Linkage with established health-care datasets helped to enhance patient identification and minimise attempts to contact deceased or previously treated individuals. From September to November 2018 each ODN was provided with a local list of diagnosed individuals. ODNs were asked to perform further data quality checks through local systems and then write to each individual’s GP to inform them that the individual would be contacted by the ODN to offer confirmatory HCV PCR testing, assessment and treatment unless the GP advised otherwise. Outcomes of interest were receipt of treatment, a negative PCR result, and death. Data were collected in 2022.
Of 176,555 individuals with a positive HCV laboratory report, 55,329 individuals were included in the exercise following linkage to healthcare datasets and data reconciliation. Participants in the study had a median age of 51 years (IQR: 43, 59), 36,779 (66.5%) were males, 47,668 (86.2%) were diagnosed before 2016 and 11,148 (20.2%) lived in London. Of the study population, 7,442 (13.4%) had evidence of treatment after the re-engagement exercise commenced, 6,435 (11.6%) were reported as PCR negative (96% had no previous treatment records), 4,195 (7.6%) had prescription data indicating treatment before the exercise commenced or were reported to have been treated previously by their ODN, and 2,990 (5.4%) had died. The status of 32,802 (59.3%) people remains unknown.
A substantial number of those included had treatment recorded after the exercise commenced, however, many more remain unengaged. Evaluation of the exercise highlighted areas that could be streamlined to improve future exercises.
Peer Review reports
The introduction of direct acting antiviral (DAA) treatments for the Hepatitis C virus (HCV), which are known to cure HCV in the majority of those treated [ 1 , 2 , 3 ], shifted the World Health Organisation (WHO) global strategy to the elimination of HCV (curing 80% of those diagnosed) as a public health threat by 2030 [ 4 ]. The UK government has committed to this strategy, with the National Health Service England (NHSE) having an ambition to eliminate HCV ahead of the 2030 goal [ 5 , 6 , 7 ]. Part of this commitment involves efforts to re-engage people previously diagnosed but no longer actively accessing services, aligning with targets to reduce both incidence of and mortality from viral hepatitis [ 8 ].
HCV infection in England is primarily driven by injecting drug use, the reported risk factor for 77% of infections, with a third of people living with chronic HCV currently injecting drugs [ 9 ]. Engagement in services for people who inject drugs (PWID) was historically low and characterised by mistrust and discrimination [ 10 ].
There have been significant efforts to (re)test, (re)diagnose and (re)treat those living with chronic HCV since DAAs became widely available. In England, between 2016 and 2021, 73% of people with a positive HCV RNA result had a record indicating DAA treatment initiation and 47% had a record indicating sustained virologic response (SVR) (HCV not detected in the blood 12 weeks after completing treatment) [ 6 ]. As a result, and through concerted efforts by partners across community, government and non-government groups, modelling estimates show a 45% decrease in HCV prevalence in England since 2015 [ 6 ]. Mortality and morbidity associated with end stage liver disease (ESLD) and hepatocellular carcinoma (HCC) have declined in England, surpassing the WHO’s target for reduction in mortality (10% reduction between 2015 and 2020, and 65% by 2030) [ 9 ]. Successful treatment has also led to significant improvements in quality of life [ 11 ].
However, England had a large population of people known to be living with chronic HCV before the advent of DAAs [ 9 ]. The frequently asymptomatic nature of HCV infection meant that many individuals may not have been aware that they had previously acquired HCV. Prior to DAA availability, the limited treatment options had poor side effect profiles and relatively poor outcomes [ 12 , 13 ]. As a result, many people living with HCV never accessed treatment services or, if they did, were unable to complete treatment and/or subsequently disengaged with services [ 14 ]. To support people previously diagnosed with HCV to be treated for their infection with DAAs, the UK Health Security Agency (UKHSA), in partnership with NHSE, launched a national ‘HCV patient re-engagement exercise’ to help find and support engagement in care for these individuals by collaborating with the Operational Delivery Networks (ODNs). ODNs are formal NHSE structures in which providers, commissioners and patients work together to optimise healthcare including routine care and treatment of people with HCV infection. ODNs mainly focus on coordinating patient pathways between providers over a wide area to ensure patients’ access to specialist resources and expertise [ 15 ]. This re-engagement exercise was launched in collaboration with peer support and patient advocacy groups who co-produced patient-facing resources, GP letters and outreach services [ 15 ].
In this paper we (a) describe the implementation of the HCV re-engagement exercise, and (b) report on the quantitative process and outcome evaluation of using laboratory surveillance data as a prompt for re-engagement into HCV care and increasing treatment uptake.
Routine laboratory reports of HCV diagnosis (defined as the detection of HCV antibody (anti-HCV) and/or HCV RNA) to UKHSA by diagnostic laboratories were used to identify individuals diagnosed with HCV between 1996 and 2017 ( n = 176,555).
Laboratory HCV reports have been submitted to UKHSA and predecessor organisations from NHS laboratories through surveillance forms or electronically since 1990, with better coverage and more streamlined reporting systems since 1996. Reporting completeness further improved when laboratory notification of a diagnosis of viral hepatitis became mandatory in 2010. It is not possible to consistently distinguish those with active infection (based on a positive HCV RNA result) from those with cleared infection as the system collects mainly anti-HCV results, and so laboratory ‘confirmed’ cases are a mixture of those with current and cleared infections. Laboratory reports include basic demographics.
A number of steps were taken to clean, reconcile and link data to generate patient lists. (Fig. 1 ) Of the 176,555 individuals with an HCV diagnosis recorded since 1996, 42,426 were excluded as minimal identifiable data was not available (i.e., name, date of birth, sex, NHS number). As laboratory data were submitted to UKHSA for surveillance purposes rather than for direct patient care, the reporting and completeness was variable. Data completeness was 80.2% for last name, 80.5% for first name, 98.2% for date of birth, 98.0% for sex, and 63.8% for NHS number.
Data flow and matching steps to generate the lists for ODNs. * Linking variables: NHS number, first name, last name, date of birth, and sex
We performed three linkage steps. First, individuals with names, date of birth, and/or NHS number (134,129) were linked to the NHS spine (Personal Demographics Service (PDS) – the national master database of all NHS patients in England) to cross-check identifiable information and to identify their current registered GP. Anyone in England can register with a GP to access NHS services [ 16 ]. However, this is not compulsory. In total, 100,026 individual records were linked to the spine via NHS number, and 14,461 were linked through alphanumeric matches. Of these, 7,404 were excluded due to a non-perfect link on name, date of birth or sex between the information reported on the spine and that reported with the diagnosis record.
Second, through linking to registered deaths provided by the Office of National Statistics (ONS) and/or a died flag in the NHS spine, 20,112 of the 107,083 individuals believed to have died were excluded, with a further 7,571 excluded who were not registered with a GP or who registered with a GP outside England.
Finally, the remaining individuals (79,400) were linked to the HCV patient registry and treatment outcome database (NHSE registry), which stores records of all individuals referred to ODNs for DAAs. A further 23,370 individuals already known to the ODNs were excluded as a result, as were those first diagnosed after 2017 ( n = 701), leaving details of 55,329 individuals to be distributed to the ODNs. Individuals were assigned to an ODN using their current residential postcode or registered GP postcode retrieved through linking to the NHS Spine.
Additional flags were added to the patient lists if an individual was also found on other surveillance and healthcare datasets e.g. sentinel surveillance of blood-borne virus testing (SSBBV), Hospital Episode Statistics (HES), the NHS Blood and Transplant (NHSBT) registry, to add assurance of further evidence of HCV testing and care, to validate personal confidential data (name, date of birth, sex, NHS number) and to avoid sending letters to individuals not requiring any intervention (e.g., those who had already had a liver transplant).
All data processing and linkage was done using Microsoft SQL Server.
Between September - November 2018, UKHSA, through a secure electronic file transfer platform, provided each ODN with a list of eligible individual residents in their ODN area. UKHSA published guidance to GPs and ODNs, patient and GP leaflets, and template letters, co-developed with the Hepatitis C Trust and NHSE, to support the re-engagement exercise [ 15 ].
ODNs undertook further quality checks of the data with their local IT systems (e.g., laboratory, patient administrative, and treatment databases) to verify the HCV status and contact details of the individual and wrote to each individual’s GPs to inform them that they would be contacting their patients to offer confirmatory testing (HCV RNA) and assessment for HCV treatment, unless the GP raised concerns. The Memorandum of Understanding (MoU) stipulated that ODNs were responsible for local information and clinical governance, including provision of appropriate care pathways.
An evaluation of the re-engagement exercise was developed with four key phases: phase 1: baseline survey (through structured interviews) of the capacity of ODNs and their plans to use the patient lists for case-finding initiatives [ 17 ]; phase 2: quantitative assessment with process and outcome indicators; phase 3: qualitative assessment of public and professional perspectives of the re-engagement exercise; and phase 4: economic assessment of the cost effectiveness of the intervention.
This paper focuses on phase 2. Process indicators included whether contact was made with an individual, and the reasons why contact was not made. Outcome indicators include treatment uptake, and reasons for non-treatment (e.g., PCR negative, previous treatment, or death). (Table 1 ) To measure process and outcome indicators, ODNs were asked to (i) complete standardised monitoring and evaluation spreadsheets (Supplementary information 1 ), and (ii) to flag ‘re-engagement exercise’ as the reason for referral on the NHSE HCV patient registry and treatment outcome database.
The exercise was disrupted by the COVID pandemic with data returned between March and August 2022. Eleven of the 22 ODNs returned the data in monitoring and evaluation spreadsheets and in quarterly reports to NHSE on activity. Because of low response or missing data in the monitoring and evaluation spreadsheets from some ODNs, we supplemented information (for all ODNs including those that provided partial information and those that did not respond) by re-linking individuals on the lists: (i) to the NHSE registry to identify those who had received treatment after the list was shared with ODNs and/or had ‘re-engagement exercise’ flagged as the reason for referral and (ii) to the ONS deaths database to determine any individuals who had subsequently died.
For individuals included in the final lists to ODNs, we calculated counts and proportions of different socio-demographic characteristics.
We subdivided the dataset into three groups based on individuals with data reported on: (i) both outcomes and processes (e.g., whether contact was attempted); (ii) outcomes but not processes; and (iii) no outcomes or processes. We report on outcomes from the re-engagement exercise for the whole cohort and for these three groups. We also present flow charts and outcomes by these three groups.
For individuals remaining with an unknown outcome, we report on the distribution of unknown status by age, sex, and year of diagnosis.
We also present counts and proportions for ICD-10 causes of death and contributory factors as reported in ONS data. Logistic regression models were used to determine factors associated with receipt of treatment and death. Bivariate analyses were conducted with variables which could have a plausible association. All variables with p < 0.1 were included in the multivariable model with parsimony achieved using Wald tests.
Doctors and laboratory directors working in the private or public sectors are mandated by law to report any new diagnoses of HCV as it is a notifiable organism (however it is unknown whether this stipulation is always followed) [ 18 ]. The UKHSA collects this information for disease surveillance and to control and prevent the spread of infectious diseases under Sect. 251 of the NHS Act 2006 and the Health Service (Control of Patient Information) Regulations 2002 (regulation 3 / ‘Sect. 251 support’). This allows UKHSA to process personal confidential data without consent. For this exercise, UKHSA sought specific Caldicott approval to share historic laboratory surveillance data with ODNs. The conservative, deterministic linkage process described above was followed to mitigate information governance risks identified during the ethics review process which included (a) accidental or inadvertent disclosure; (b) incidental or inappropriate notification; (c) incorrect diagnoses due to erroneous test coding or poorer performance of older assays; and (d) missed diagnoses due to underreporting and/or incomplete or incorrect information. In its approval, UKHSA’s Caldicott panel indicated that the information governance and confidentiality risks specified within the application were outweighed by the public health benefits in terms of providing treatment to people who may otherwise suffer morbidity and mortality from untreated HCV related liver disease, and by preventing onward transmission of HCV.
Prior to release of patient identifiable data to the ODNs, each ODN signed a MoU with data sharing agreement which outlined that these data should be used solely for the purpose for which special Caldicott permission was received, and not, for example, used for research or shared with academic or commercial entities. The MoU also restated the recipient’s responsibilities about data security, storage and legitimate sharing of data with those involved in direct patient care, as well as the steps that needed to be taken to mitigate information governance risks.
Re-engagement lists varied in size ranging from 1,050 individuals sent to the Leicester ODN to 5,429 individuals sent to the Greater Manchester and Eastern Cheshire ODN (Supplementary information 2 ).
Of 55,329 individuals included in the re-engagement exercise, 36,779 (66.5%) were males, the group had a median age of 51 years (IQR:43, 59) at the time of analysis (2023), 47,668 (86.2%) were diagnosed before 2016, and 11,148 (20.2%) were resident in London. (Table 2 )
Figure 2 summarises the processes and outcomes of the re-engagement exercise. The 11 ODNs that returned data accounted for 25,813 (46.7%) of all the individuals included in the re-engagement exercise. (Table 2 ) Returned data varied in detail and completeness with two ODNs returning outcome data but no process data (e.g., number of people contacted).
Alluvial plot of the cascade of the re-engagement exercise
Of eleven ODNs that did not return data, 4 (36.4%) reported preliminary findings in quarterly ODN reports, and 1 (9.1%) had published results from the re-engagement exercise which showed significant variation in its implementation [ 19 ].
Of 25,813 individuals from ODNs that returned data, 9,197 (35.6%) had process indicators reported in their record of whom 4,750 (51.6%) were contacted by their ODN. Supplementary Fig. 1 reports on outcomes for individuals with process indicators. Of these, initial investigations excluded 163 individuals who had died and 17 children, 2,317 (48.8%) responded, 2,215 (46.6%) did not respond (115 letters returned to the ODN) and 38 (0.8%) could not be further engaged for multiple reasons. Of the 4,447 with process indicators who had not been contacted, reasons for no contact included: known to be PCR negative (1,612, 36.2%); receipt of treatment before the exercise (264, 5.9%); known to ODN but no evidence of treatment (413, 9.3%); known to ODN and treated (377, 8.5%); transferred care (167, 3.8%); awaiting results (4, < 0.1%); GP indicated inappropriate to contact (12, 0.3%); emigrated (3, < 0.1%). A further 108 (2.4%) individuals had not been contacted as the ODN was still awaiting a GP response. Finally, 1,387 individuals could not be contacted by the ODN either because ODNs did not have up-to-date contact details (513, 11.5%), or they remained unknown to the ODN (no record found) and were therefore considered to be ‘not engaged’ with services (874, 19.6%) (Supplementary Fig. 1 ).
Table 3 summarises outcomes for all individuals. Of 55,329 individuals included in the re-engagement exercise, as of August 2022, 7,442 (13.4%) had accessed treatment since the re-engagement exercise commenced, 2,990 (5.4%) were found to have died, 6,435 (11.6%) were reported as PCR negative (96% of whom had no previous treatment records Footnote 1 ), 4,195 (7.6%) had prescription data indicating treatment before the exercise commenced or were reported as previously treated by their ODN, 411 (0.7%) declined to engage, 276 (0.5%) had not yet attended a planned ODN appointment, 167 (0.3%) were reported to have transferred their treatment elsewhere, 35 (0.1%) were awaiting blood test results, and for 29 a decision had been made not to treat (12 (< 0.1%) had emigrated, 9 (< 0.1%) were inappropriate to contact and 8 (< 0.1%) had a liver related event). The remaining 33,349 (60.3%) people had an unknown status (547 of these were children). (Table 3 )
Among those where contact was attempted and who responded (2,317/4,750), 939 (40.5%) were treated for HCV after the exercise commenced, 649 (28.0%) were already PCR negative, 418 (18.0%) had received treatment prior to the re-engagement exercise, 276 (11.9%) had not yet received treatment and required further follow-up, 34 (1.5%) were awaiting blood test results, and there was 1 (< 1%) decision not to treat. Of those where contact was attempted, there were a further 38 decisions not to treat (21 refused treatment, 9 were not treated due to medical reasons and 8 had emigrated) (Supplementary Fig. 1 ).
Of 16,616 individuals with outcomes but no process data, 2,146 (12.9%) had been treated since the beginning of the re-engagement exercise (post-2017), 4,437 (26.7%) were PCR negative, 1,692 (10.2%) had previously received treatment (pre-2017), and 7,585 (45.6%) [11 reported as PCR positive but not treated and 7,574 who remained unknown to the ODN] were considered to be ‘not engaged’ with services (Supplementary Fig. 2 ).
Through linking to ONS death registrations and the HCV patient registry and treatment outcome database (NHSE registry), of the 29,516 individuals where no process or outcome data was returned, 1,623 (5.5%) had died, 1,949 (6.6%) had been previously treated (pre-2017) and 4,061 (13.8%) had been treated since the commencement of the re-engagement exercise (post-2017) (Supplementary Fig. 3 ).
Of 55,329 individuals in the exercise, 7,621 (13.8%) had evidence of treatment after the exercise (7,442 were still alive). Females [aOR: 0.66 (95% CI: 0.63–0.70)], and older individuals [e.g., 55-64-year-olds aOR: 0.66 (0.62–0.71) compared to 45-54-year-olds] were less likely to receive treatment. Those diagnosed after 2015 [aOR: 1.35 (1.25–1.45)] and those living outside London [e.g., North-West aOR: 1.99 (1.83–2.17)] were more likely to receive treatment. (Table 4 )
Of 55,329 individuals included in the re-engagement exercise, 33,349 (60.3%) continued to have an unknown outcome (547, 1.6% of whom were children). They had a median age of 51 years (IQR: 43, 60), 21,659 (64.9%) were male, and 26,312 (78.9%) were diagnosed between 2006 and 2017, the largest proportion of whom (12,447, 37.3%) were diagnosed between 2011 and 2015.
For ODNs that returned data, of 25,813 individuals included in the exercise, 11,466 (44.4%) continued to have an unknown status (168 were children). They had a median age of 52 years (IQR: 44, 61), 7523 (65.6%) were male, and 9,117 (79.5%) were diagnosed between 2006 and 2015, the largest proportion (4,396, 38.3%) between 2011 and 2015.
Of 2,990 individuals who had died, 2,104 (70.4%) were males and median age at death was 54 years (IQR: 46, 63). The underlying cause was missing for 515 (17.2%) deaths. The leading single underlying cause of death, where available, was HCC accounting for 183 (7.4%) of deaths with a reported underlying cause, liver disease accounted for 300 (12.1%), and viral hepatitis for 88 (3.6%) of deaths. There were 571 (19.1%) reported liver related deaths, with HCV indicated as a contributory cause for 271/571 (47.5%). HCV was a contributory factor for 457 (15.3%) of all deaths while HCC and ESLD were contributory factors for 222 (7.4%) and 227 (7.6%) of deaths respectively (Supplementary information 3 ). In logistic regression models, we found that older individuals, males, those diagnosed after 2015, and those living outside London were more likely to have died (Supplementary information 4 )
We report on a nation-wide exercise utilising national diagnostic testing surveillance data and established clinical networks to re-engage individuals who previously tested positive for HCV and to offer treatment to those confirmed HCV RNA positive. Following this collaborative effort between UKHSA and the NHSE ODNs, 7,442 (13% increasing to 18% when we exclude previously treated, PCR negative and those who died) individuals who were previously not engaged in care were prescribed HCV treatment. These individuals are estimated to represent 10% of the total number of individuals treated in England since 2015. We also found that 2,990 (5%) individuals had died of whom 15% had HCC and/or ESLD recorded as a contributing factor on their death certificate. Overall the exercise was unable to directly re-engage 33,349 (60%) of identifiable individuals with known HCV antibody or RNA positivity thought to be alive.
Our overall findings are similar to those published by Birmingham ODN which reported modest (11.3%) response rates to letters and low (25%) confirmed SVR numbers [ 19 ]. Similar exercises conducted in Wales [ 20 ], Netherlands [ 21 , 22 ], and France [ 23 ] reported re-engagement rates of 23% and treatments rates ranging from 8 to 15%. The Relink program used medical record review to identify eligible participants, re-engaged 33% of 11,163 participants in six countries, and treated 6% [ 24 , 25 ]. Similar to this exercise, the Trap Hep C programme in Iceland addressing an infected population of 1,100 compared to 81,000 in England [ 4 ], used cross-referenced surveillance and laboratory data and managed to re-engage all 24 participants achieving SVR12 for 83% [ 26 ]. A clinical trial in the Canary Islands found that phone calls were more effective than letters for re-engaging people previously diagnosed with HCV [ 27 ]. Participants were less likely to re-engage if they had a history of drug use, tested in the pre-DAA era, and had no prior specialist evaluation [ 28 ]. Other studies have used a range of approaches to encourage re-engagement in HIV care, including text messaging and physical tracing. [ 29 , 30 , 31 , 32 , 33 ]
Individuals treated since the exercise included individuals already known to the ODN, and individuals not known, who might have been unaware of their infection, aware of their infection but not engaged with healthcare services, and/or unaware of the emergence of new, better tolerated and more effective treatments. Our findings suggest that Londoners, females, the very young and very old might benefit from a targeted effort to get them onto treatment. The number of individuals treated suggests that using national surveillance data as the basis for patient re-engagement exercises has some utility, but requires further interrogation of additional data sources to refine and validate the data, engagement from all stakeholders, with extensive follow up and local data checks by the ODNs. In some instances, despite positive re-engagement some individuals refused treatment. It is important that these individuals have continuing support and access to treatment should they change their mind.
Approximately 12% of individuals included in the exercise were found to be PCR negative of whom only 4% had evidence of treatment. This could reflect several mechanisms including spontaneous clearance of infection, [ 34 ] treatment outside the NHS (privately or outside England), or failure to record treatment. Given the mix of antibody and PCR tests in the laboratory surveillance dataset, the study would have included some individuals without an active infection. For example, a study conducted in GP practices in Southwest England found only 40% of participants recorded as antibody positive were confirmed to be vireamic [ 35 ]. This group might have been less likely to engage with the exercise if they knew they had cleared HCV. The introduction of routine reflex PCR testing of antibody positive samples and point-of-care PCR testing in England [ 19 , 36 ] should eliminate this as an issue for future similar exercises.
The exercise also revealed that 5.4% of individuals included in the exercise had died. A substantial proportion had HCV, ESLD and/or HCC as either a direct or contributory cause of death. Liver related deaths with HCV reported as a contributory cause were similar to those reported in another study [ 37 ]. Similar to other studies, we found that males, and older individuals were more likely to have died [ 38 , 39 ]. Those outside London were also more likely to have died consistent with mortality trends from ONS [ 40 ], as were those diagnosed more recently. Those diagnosed recently could have a higher proportion of active injection drug use which is the primary route of infection in England [ 6 ]. However, we did not have access to this or other data such as biomarkers for disease progression, social economic status, and other health risk behaviours (e.g. alcohol use) which are consistent predictors of mortality in people with HCV [ 41 , 42 ]. The advent of DAAs has rendered HCV a curable disease in the vast majority of cases, so these deaths might have been avoided with earlier engagement in care. These findings illustrate the importance of the test and treat models, and ongoing work by NHSE to simplify the care pathway to ensure that people testing positive for HCV RNA have quick and easy access to treatment.
We found that 60% of those on the lists shared with ODNs still had an unknown outcome. The majority of this group were males, 40 years or older, most of whom had been diagnosed between 2011 and 2015. However, females contributed a larger proportion: 63.0% of females vs. 58.9% of males did not re-engage. Another study reported lower re-engagement for individuals diagnosed in the era preceding widespread use of DAAs [ 28 ]. In our study, varied levels of re-engagement likely represent implementation and individual-level challenges. Implementation challenges include varying ODN engagement with 11 of the 22 ODNs not reporting data, thus limiting our ability to fully evaluate the exercise. Secondly, there was significant heterogeneity in the implementation approaches used by ODNs. In the phase 1 evaluation, ODNs reported several obstacles including a lack of dedicated human resources and funding which may have contributed to this variability. Thirdly, due to varying data completeness, many individuals could not be found in any of the records ODNs cross-checked or could not be reached due to a lack of up-to-date contact details. Studies suggest that better infrastructure could improve re-engagement exercises, including simple fixes such as regular data sharing between health facilities [ 43 ]. Many printed letters, which were the main mode of contacting individuals in the exercise, were unanswered or not delivered, and letters have been shown to be less effective than other methods e.g., phone calls [ 27 ]. Finally, the exercise was designed to make successful re-engagement independent of GP involvement as GPs are often overburdened and have competing priorities [ 44 , 45 ]. However, the largest proportion of diagnoses in laboratory surveillance are made through primary care [ 46 ], and studies have shown higher treatment initiation and SVR rates for participants treated in primary care [ 47 ]. Closer integration of primary care could result in better outcomes as some studies in primary care have shown moderate success [ 35 ]. Additionally, there are several initiatives being implemented to reach this population including opt-out bloodborne virus testing in emergency departments [ 48 , 49 ], and targeted testing in GPs [ 35 , 50 ].
Individual barriers affecting re-engagement could include anticipated stigma [ 51 ], mistrust of institutions charged with their care [ 52 ], and the mobility and transience of some people affected by HCV as demonstrated in other studies [ 53 , 54 ].
Factors such as dissatisfaction with services, insufficient knowledge of HCV and treatment outcomes, complex needs, competing priorities and concerns about treatment side effects may both result in disengagement and affect re-engagement [ 55 ]. Service design should minimise barriers and maximise engagement opportunities, using approaches informed by behavioural science. Services must adapt to cater to transient and underserved populations and more complex cases using a more patient-centred approach [ 56 , 57 ]. Awareness campaigns are also necessary to educate the wider public about new treatments to enable them to objectively assess their own risk [ 58 ].
A qualitative evaluation of the re-engagement process might help identify factors leading to more effective engagement of ODNs such as monetary incentivisation, [ 50 ] and more effective networked data infrastructure. Implementation could be improved with more quality control and refining of datasets before they are shared, support for ODNs to perform data cross-checks, capacity building, and implementation toolkits to facilitate future exercises.
Strict criteria were used to minimise data errors in creating the lists provided to the ODNs and mitigate information governance risks. A further 69,472 individuals were excluded from the initial exercise due to lack of sufficient identifiers or data inconsistencies (Fig. 1 ) highlighting the importance of comprehensive data requiring further investment.A proportion of these individuals are likely to be viraemic and, because they are so numerous, without treatment, the goal of HCV elimination will remain challenging [ 4 ].
Reasons for the variation in ODN response are not well understood and merit further investigation. Qualitative in-depth interviews are planned to understand the causes of variation to gain insights that could optimise future re-engagement efforts. There is a pressing need to involve patients to understand their experiences of the exercise. While ODNs indicated that the exercise appeared acceptable to patients and reported no adverse consequences, [ 17 ] qualitative research is planned to explore participants’ experiences. A separate exercise to re-engage children is also being conducted by the paediatrics team.
There are several key strengths of the re-engagement exercise. Firstly, the data used was diagnostic testing data for England which was made notifiable for HCV in 2010 and therefore should include all diagnostic tests for HCV from that time, as well as a majority of those reported prior to 2010. Secondly, multiple healthcare databases were used to build the re-engagement lists, allowing for triangulation of data especially concerning HCV diagnoses, treatment and death, further enhanced by local checks undertaken by ODNs. Data linkage permitted the creation of a more comprehensive database than would have been obtained relying solely on ODN reports [ 59 , 60 ].
However, the exercise also had some limitations. Firstly, there was varying engagement from ODNs. As such, our analyses were restricted by the amount and quality of data returned by ODNs. Secondly, information governance issues especially between laboratories and ODNs significantly hampered the exercise. Third, many individuals included on the basis of a positive HCV antibody test may have cleared HCV infection spontaneously or through private treatment. Fourth, we cannot attribute all treatment initiations reported to the re-engagement exercise as this reason was not consistently recorded in the NHSE registry. Finally, it is important to acknowledge the impact of COVID pandemic on the exercise.
In conclusion, this exercise was a substantial and extensive undertaking facilitated by access to key data resources and the participation of multiple organisations. The use of HCV surveillance data to re-engage individuals into care resulted in a sizeable number of people with known HCV infection accessing treatment. Further work is needed to investigate how those engaged differ from those whose infection and treatment status remain unknown. Repeat re-engagement exercises with improved implementation and alternative, complementary elimination strategies should be considered.
No datasets were generated or analysed during the current study.
Only 258 (4%) of individuals reported as PCR negative had evidence of treatment in the NHSE registry [19 (7.3%) 2017 or earlier, 156 (60.5%) in 2018 and 83 (32.2%) missing].
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We would like to thank Mary Ramsay, Mark Gillyon-Powell, and Beatrice Emmanouil for their support in planning, implementation, and evaluation of the exercise. We acknowledge members of the NIHR HPRU in BBSTI Steering Committee: Professor Caroline Sabin (HPRU Director), Dr John Saunders (UK HSA Lead), Professor Catherine Mercer, Dr Hamish Mohammed, Professor Greta Rait, Dr Ruth Simmons, Professor William Rosenberg, Dr Tamyo Mbisa, Professor Rosalind Raine, Dr Sema Mandal, Dr Rosamund Yu, Dr Samreen Ijaz, Dr Fabiana Lorencatto, Dr Rachel Hunter, Dr Kirsty Foster and Dr Mamoona Tahir.
The research was funded by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Blood Borne and Sexually Transmitted Infections at University College London in partnership with UK HSA. The views expressed are those of the authors and not necessarily those of the NIHR, the Department of Health and Social Care or UKHSA.
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David Etoori & Caroline Sabin
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David Etoori, Ruth Simmons, Monica Desai, Caroline Sabin, Sema Mandal & William Rosenberg
Sexually Transmitted Infections and HIV Division, Blood Safety, Health Security Agency, 61 Colindale Avenue, NW9 5EQ, Hepatitis, London, UK
Ruth Simmons, Monica Desai, Avelie Stuart & Sema Mandal
Barts Liver Centre, The Blizard Institute, QMUL, London, UK
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The study was conceived by SM and RS. SM led the planning and implementation of the re-engagement exercise and the evaluation approach. RS conducted data processing and linkage and prepared the ODN lists. GRF supported planning and helped manage the ODNs response to the exercise. The analysis plan was designed by DE with input from WR, SM, CS, RS, and MD. DE conducted the analyses and drafted the manuscript with input from AS and all the authors. All the authors reviewed and approved the final manuscript.
Correspondence to David Etoori .
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Informed consent was not obtained from participants. The UK Health Security Agency has approval to handle public health surveillance data under Sect. 251 of the NHS Act 2006 and Regulation 3 of the Health Service (Control of Patient Information) Regulations 2002. This allows UKHSA to process personal confidential data without consent. Sharing of historic laboratory surveillance data with ODNs was approved by the UKHSA Caldicott panel.
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CS has received funding for membership of Advisory Boards, Data Safety and Monitoring Panels and for the preparation of educational materials from Gilead Sciences, ViiV Healthcare, Janssen-Cilag and MSD. All other authors declare no competing risks.
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Etoori, D., Simmons, R., Desai, M. et al. Results from a retrospective case finding and re-engagement exercise for people previously diagnosed with hepatitis C virus to increase uptake of directly acting antiviral treatment. BMC Public Health 24 , 2427 (2024). https://doi.org/10.1186/s12889-024-19919-3
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Late-onset multiple sclerosis (LOMS), defined as the development of MS after the age of 50, has shown a substantial surge in incidence rates and is associated with more rapid progression of disability. Besides, studies have linked tobacco smoking to a higher chance of MS progression. However, the role of smoking on the risk of developing LOMS remains unclear. This study aims to evaluate the possible association between lifetime exposure to cigarette and waterpipe smoking, drug abuse, and alcohol consumption and the risk of LOMS.
This population-based case-control study involved LOMS cases and healthy sex and age-matched controls from the general population in Tehran, Iran. The primary data for confirmed LOMS cases were obtained from the nationwide MS registry of Iran (NMSRI), while supplementary data were collected through telephone and on-site interviews. Predesigned questionnaire for multinational case-control studies of MS environmental risk factors was used to evaluate the LOMS risk factors. The study employed Likelihood ratio chi-square test to compare qualitative variables between the two groups and utilized two independent sample t-test to compare quantitative data. Adjusted odds ratio (AOR) for age along with 95% confidence intervals (CI) were calculated using matched logistic regression analysis in SPSS 23.
Totally, 83 LOMS cases and 207 controls were included in the analysis. The female to male ratio in the cases was 1.5: 1. The mean ± SD age of 83 cases and 207 controls was 61.14 ± 5.38) and 61.51 ± 7.67 years, respectively. The mean ± SD expanded disability status scale (EDSS) score was 3.68 ± 2.1. Although the results of waterpipe exposure had no significant effect on LOMS development (P-value: 0.066), ever cigarette-smoked participants had a significantly higher risk of developing LOMS than those who never smoked (AOR: 2.57, 95% CI: 1.44–4.60). Furthermore, people with a history of smoking for more than 20 years had 3.45 times the odds of developing MS than non-smokers. Drug and alcohol abuse were both associated with LOMS in our study; of which opioids (AOR: 5.67, 95% CI: 2.05–15.7), wine (AOR: 3.30, 95% CI: 1.41–7.71), and beer (AOR: 3.12, 95% CI: 1.45–6.69) were found to pose the greatest risk of LOMS, respectively.
For the first time, we identified smoking, drug, and alcohol use as potential risk factors for LOMS development. According to the global increase in cigarette smoking and alcohol use, these findings highlight the importance of conducting interventional approaches for prevention.
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Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease that affects the central nervous system by infiltration of immune cells and inflammatory demyelination of white matter [ 1 ]. Considered the most common chronic demyelinating disorder, MS leads to disability and a significant decline in quality of life, especially in young individuals [ 2 ]. Although the exact etiology is still unclear, research has increasingly focused on identifying potential risk factors that may contribute to its development and progression. Factors such as previous EBV infection, vitamin D deficiency, obesity, and smoking have been proposed as potential risk factors for MS development [ 3 ].
The onset of MS usually occurs during the third to fourth decade of life [ 4 ]. However, some patients may experience symptoms beyond the age of 50 [ 5 ]. Recent studies have indicated that late-onset multiple sclerosis (LOMS) is more prevalent than previously believed, with estimates ranging between 4% and 9.4%. These findings challenge the notion that LOMS is of rare occurrence [ 6 , 7 ]. In light of existing literature, progressive patterns of MS are more common in LOMS patients [ 8 , 9 ]. Moreover, the diagnosis of LOMS can be challenging for clinicians, as many diseases in the elderly may present with similar characteristics [ 10 ]. This highlights the importance of early diagnosis, understanding the disease characteristics, and identifying its associated risk factors.
In the past few years, emerging epidemiological research has suggested a possible link between smoking and MS. Cigarette smoking amplifies inflammatory responses, diminishes specific components of the immune system, and enhances the propensity for infection [ 11 ]. Previous studies have also hinted at a possible connection between smoking and MS through the presence of low serum vitamin D levels and inadequate dietary vitamin D intake among smokers [ 12 ]. The duration and intensity of smoking play significant roles in the dose-dependent risks associated with MS, and the adverse effects gradually decline upon smoking cessation [ 13 , 14 ]. Waterpipe smoking has also been recognized as a risk factor for the development of MS [ 15 ]. Notably, the role of alcohol consumption in MS remains debated, with studies supporting both risk and protective viewpoints [ 12 , 16 ]. Some recent studies have also mentioned substance use as a potential risk factor for MS, although specific details are not provided [ 15 ]. However, there is limited evidence regarding the risk factors associated with LOMS.
This study aims to explore the potential effect of tobacco smoking, alcohol consumption, and substance abuse as risk factors for LOMS.
Study design.
A population-based case-control study was carried out during 9 months from November 2022 to July 2023 in Tehran to investigate the potential risk factors of late-onset MS. The study employed a hybrid approach, combining both in-person and remote data collection methods.
The source population of our study was all residents aged 50 years and above residing in one of the 22 districts within the Tehran municipality for a minimum of two years. Cases were defined as confirmed LOMS patients according to the 2017 McDonald criteria, registered at our official MS registry, the nationwide MS registry of Iran (NMSRI) [ 17 , 18 ]. Besides, controls were healthy individuals within the source population with no history of MS, selected randomly through an age-matched randomization method from various areas of Tehran. Overall, 97 registered cases and 230 matched controls were contacted for further investigations and interview. Individuals with cognitive impairment or a lack of willingness to participate in the interview were excluded. Controls who presented any form of other neurological disease were also excluded.
Clinical characteristics of LOMS cases were extracted from NMSRI to complete a structured questionnaire, designed specifically for multinational case-control research on environmental risk factors associated with MS [ 19 ]. Telephone interviews were also performed by four well-trained interviewers to gather supplementary data on the cases. Moreover, two interviewers conducted a face-to-face interview with the general population as the control group, using the same questionnaire.
Participants were asked to fill out the study questionnaire comprising demographic items such as age, sex, marital status, the highest level of education, and self-rated health status - scored from 1 (the lowest) to 5 (the highest)-, and their history of cigarette and waterpipe smoking, substance (opioids, cannabis, stimulants, hallucinogen) use, and alcohol (whisky/vodka, beer, and wine) consumption across the life course.
The history of cigarette smoking was considered positive if the participant smoked cigarettes for at least 6 months or more than 180 cigarettes in total. Substance use and alcohol consumption were positive if participants used them at least once per month for more than 6 months, while for waterpipe it was considered at least once per week for more than 6 months [ 13 , 20 ].
Quantitative data was described using mean and standard deviation, whereas qualitative data was described using number and percentage. Likelihood ratio chi-square test was utilized to compare qualitative variables between two groups and two independent sample t-test was employed to compare quantitative data. Crude and adjusted odds ratio (OR) and 95% confidence interval (CI) were also used to check the effect size of independent variables on dependent variables. All analyses were performed using Stata software version 14 and at a significance level of 0.05.
Each participant was thoroughly informed about his/her role in the study as well as the purpose of the research, and their probable questions about the study were answered. All participants were required to give verbal consent to be informed that their personal information is kept secure. Those who were unwilling to take part in our study were excluded. The ethics committee at Tehran University of Medical Sciences approved the current study by the code: IR.TUMS.NI.REC.1402.028. Furthermore, all the steps taken in this study adhere to the principles outlined in the Declaration of Helsinki.
Overall, 83 cases with LOMS and 207 controls were included. The demographic variables are compared between the two groups in Table 1 . The mean ± SD expanded disability status scale (EDSS) score was 3.68 ± 2.1 in cases. The results indicate that there was no significant difference between the two groups concerning marital status ( p = 0.444). Compared to the controls, the cases had less education ( p = 0.030) and a lower mean self-rated health score ( p = 0.001).
The frequency distribution of cigarette and waterpipe smoking is shown in Table 2 . There was no significant difference in the frequency of waterpipe use between the two groups (6.0% vs. 4.3%). The frequency of ever cigarette smoking in the case group was significantly higher than in the control group (36.1% vs. 18.8%), and after adjusting for age, the odds of MS in smokers were 2.57 (95% CI: 1.44–4.60, p = 0.001) times that of non-smokers. In addition, the odds of developing MS in current smokers were 4.33 (95% CI: 2.06–9.09, p = 0.001) times that of non-smokers, while those who quit smoking had no higher odds of developing MS compared to non-smokers (OR = 1.40, 95% CI: 0.62–3.17, p = 0.417). Subjects who had a history of smoking for more than 20 years had 3.45 times higher odds of developing MS than non-smokers (95% CI: 1.82–6.90, p = 0.001). Passive smoking and its duration showed no significant difference between the two groups.
Table 3 depicts the association between substance and alcohol use and LOMS development. The prevalence of opium use in patients with LOMS was significantly higher than in the control group (14.5% vs. 2.9%), and after adjusting for age, the odds of developing MS in people with a history of opium use was 5.67 (95% CI: 2.05–15.7, p = 0.001) times higher than those without a history. On the other hand, the prevalence of cannabis use in patients with LOMS were significantly lower (p-value = 0.025). There were no reports by any of our participants regarding the use of stimulants or hallucinogens.
The prevalence of alcohol consumption was significantly higher in the LOMS cases (24.1% vs. 11.6%). After adjusting for age, the results showed that the odds of developing MS in people with a history of alcohol consumption were significantly higher than that of those without a history of alcohol consumption (OR = 2.45, 95% CI: 1.26–4.76, p = 0.008). Specifically, wine (OR = 3.30, 95%CI: 1.41–7.71, P = 0.006) and beer consumption (OR = 3.12, 95%CI: 1.45–6.69, P = 0.003) were associated with an increased LOMS risk ( Table 4 and 5 ).
The present population-based case-control study reported the characteristics of 83 LOMS patients and 207 healthy controls in an Iranian population and assessed the possible role of exposure to cigarette and waterpipe smoking, drug abuse, and alcohol consumption in the risk of LOMS development. Since various risk factors can influence the age of onset and differ across various age groups, as well as different populations, we have undertaken to explore the potential influence of tobacco smoking, alcohol consumption, and substance abuse as risk factors for LOMS. For all we know, this is the first research to examine these factors in a relatively large-scale Iranian population, which makes it stand out from other national studies. Besides, the inclusion of a large control group adds to the robustness of the analysis, enhancing the reliability of the results.
The mean ± SD EDSS score was 3.68 ± 2.1 in cases, indicating a moderate level of disability. Interestingly, there was no significant difference between the two groups concerning marital status which aligns with the findings of Alsharie et al. [ 1 ] who examined PPMS cases and controls, where they also found no significant differences in marital status ( P = 0.02). Moreover, in our study, we observed that the LOMS cases had significantly lower levels of education and self-rated health compared to the control group. This finding echoes the results of studies on PPMS [ 1 ] and NMOSD [ 4 ], which reported a higher self-rated health score in controls compared to NMOSD cases. These results collectively suggest that educational attainment and self-perceived health may have an impact on various neurologic diseases, including LOMS, PPMS, and NMOSD. The differences in education levels and self-rated health between cases and controls highlight the potential influence of social and quality-of-life factors in the development and progression of neurologic conditions.
The current study also confirms the correlation between smoking cigarettes and increased odds for LOMS. The age-adjusted OR of developing LOMS was 2.57 in ever smokers and 4.33 in current smokers. However, the results could not show an association between ex-smokers and the risk of LOMS. Smoking for more than 20 years had 3.45 times the odds of developing LOMS. Although passive smoking was more prevalent in LOMS with OR of 1.79, the statistical analysis was unable to demonstrate a significant difference between the two groups. These findings broadly support the study on individuals with MS aged 40 to 69 years who reported increased OR of current smoking but not passive smoking [ 21 ]. Conversely, in a prospective cohort, current or former smoking was not significantly linked with the risk of LOMS [ 22 ].
Evidence on the risk factors of LOMS is limited. However, several studies have established that smoking is a risk factor for developing, and adverse prognosis of MS [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. Duration and intensity of smoking contribute dose-dependent to the hazards of MS and the harmful effects slowly subside after smoking cessation [ 32 ]. The attributed effects of smoking might be due to interaction with some genetic variants and subsequent activation of T cells [ 33 ]. Smoking enhances inflammatory responses, reduces some immune defenses, and increase vulnerability to infection [ 11 ]. Furthermore, smoking acts synergistically with Epstein-Barr virus antibody levels to increases MS risk [ 34 ]. In addition, components in cigarette smoke might cause direct toxic effects on neurons [ 35 ].
Despite the strong evidence, some studies using Mendelian randomization manifested no clear confirmation of smoking as environmental risk factor for MS susceptibility [ 36 , 37 ]. In contrast to our findings, some studies have reported that passive smoking and prior smoking increased the risk of MS [ 13 , 20 , 38 , 39 , 40 , 41 ]. The frequency of ever waterpipe smoking in the LOMS group was slightly more than the control group; however, the difference was not significant. This limitation is attributed to the small sample size of patients who smoked water pipes and participated in the study. The limited number of participants who engaged in this smoking method precludes definitive conclusions regarding its potential association with the outcome of interest. Contrary to the current results, some studies have reported that waterpipe smoking increases the risk of MS [ 42 , 43 , 44 ].
We also observed a significant correlation between opium use and the onset of LOMS. The odds of developing MS in people with a history of opium use was 5.67 times higher than those without a history after adjusting for age.
No study had ever assessed the effect of drugs on the LOMS. However, evaluating the impact of recreational drugs on MS revealed a significant link between drug abuse and MS onset which is in line with our findings for LOMS [ 45 , 46 ]. Conversely, no connection was observed between the abuse of opium and the onset of MS in a study, and current or past use of marijuana and MS in another study [ 47 , 48 ].
It seems that alterations in the endogenous opioid system contribute to the onset and severity of symptoms in MS patients [ 49 ]. Studies detected all three Delta opioid receptors (DOR), Mu-opioid receptors (MOR), and Kappa-opioid receptors (KOR) in T cells, B cells, and macrophages [ 50 , 51 ]. Disruptions in the balance of the T helper cells, especially decreasing the Th1/Th2 ratio are established to play a major role in the immunopathogenesis of MS [ 52 , 53 ]. Morphine can cause an alteration in Th1/Th2 ratio, cytokine expression, T cell apoptosis, and differentiation [ 54 ]. Opium addict patients have higher EDSS scores, increased fatigue severity scale, and memory impairments [ 55 ].
In our study, the prevalence of alcohol consumption was significantly higher in LOMS patients compared to healthy subjects. In addition, drinking alcohol, especially wine and beer, during adolescence and young adulthood increased the risk of LOMS. In a large cohort study conducted in England between 1999 and 2011, the risk of developing MS in any type of alcohol use, such as alcohol consumption, alcohol abuse, and dependence, was significantly increased. This investigation supported a noteworthy positive relationship between alcohol use disorders and the risk of MS [ 56 ]. However, some population-based studies, have indicated that there is a dose-dependent inverse relationship between MS and alcohol consumption [ 57 ].
In previous studies, it has been mentioned that long-term high alcohol consumption has harmful effects on the humoral and cellular immune systems [ 58 ]. Furthermore, it seems that alcohol consumption can reduce the frequency of lymphocytes, and this reduction is more pronounced in people with alcohol use disorder (AUD) [ 59 ]. Also, alcohol abuse can cause a shift in T cell phenotype by changing the surface antigens and receptors [ 59 ]. In addition, due to the augmentation in hematopoietic proliferation, the number of memory T cells may increase and the accumulation of memory T cells in different tissues increases the incidence of chronic inflammatory diseases [ 60 ]. Taken together, studies have shown that chronic T-cell lymphopenia following heavy and long-term alcohol consumption leads to increased hemostatic proliferation and activation of T cells, thereby increasing the ratio of memory T cells to naïve T cells, in contrast, moderate alcohol consumption increases the number of lymphocytes [ 59 ]. Some studies have suggested that smoking and alcohol consumption can cause increasing immunoglobulin (Ig) levels, and affect the function of microglia and astrocytes, which leads to strengthening the immunogenicity of self-proteins and finally the beginning of autoimmune responses and autoimmune diseases such as MS [ 61 , 62 ].
Because alcoholic beverages are high in energy and are considered a source of energy for consumers, most AUD suffer from malnutrition such as vitamins deficiency [ 63 ]. Likewise, vitamin D deficiency is one of the known risk factors for developing MS [ 64 ]. Hence, in AUD the immune system suffers from various methods, such as malnutrition with vitamin deficiency, immune cells (B and T lymphocyte) dysfunction, and barrier defects that can increase the occurrence of chronic diseases such as MS and Alzheimer’s [ 59 ].
However, there is considerable evidence that low to moderate consumption of alcoholic beverages such as beer and wine, which contain polyphenols, have beneficial effects on health and the immune system [ 65 ]. It was reported that neither all alcohol consumption nor wine or beer drinking, was linked to the risk of developing MS [ 66 ]. This contrast seems to be due to the difference in alcohol consumption definition in these studies (at least once per month for more than 6 months in our research versus several categories of alcohol consumption in the mentioned study).
As far as we know, the current study was the first to investigate the risk factors of LOMS in a relatively large population in the region with well-matched controls; however, it should be noted that due to the retrospective nature of case-control studies and the possibility of recall bias, no causation can be made and further studies are needed to address these limitations, to confirm the findings and to provide additional information on the topic.
It is critical to identify the risk factors contributing to the development of LOMS. In our study, cigarette smoking, alcohol consumption, and substance abuse have been recognized as possible risk factors for LOMS. However, waterpipe smoking did not demonstrate any association with LOMS. Individuals who have smoked cigarettes for more than 20 years face an elevated risk of developing LOMS. Furthermore, the consumption of alcohol, particularly wine and beer, during adolescence and young adulthood has been linked to higher odds of experiencing LOMS. According to the global increase in cigarette smoking and alcohol use, these results highlight the need for interventional preventive programs.
No datasets were generated or analysed during the current study.
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Naghmeh Abbasi Kasbi, Sajjad Ghane Ezabadi, Kosar Kohandel, Faezeh Khodaie, Amir Hossein Sahraian, Sahar Nikkhah Bahrami, Mahsa Mohammadi, Sharareh Eskandarieh & Mohammad Ali Sahraian
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Naghmeh Abbasi Kasbi: Data curation, Investigation, Writing – original draft, Writing – review & editing, Validation. Sajjad Ghane Ezabadi: Data curation, Investigation, Writing – original draft, Writing – review & editing. Kosar Kohandel: Data curation, Investigation, Writing – original draft, Writing – review & editing. Faezeh Khodaie: Data curation, Investigation, Writing – original draft, Writing – review & editing. Amir Hossein Sahraian: Data curation, Investigation, Writing – original draft. Sahar Nikkhah Bahrami: Writing- revision, review & editing. Mahsa Mohammadi: Data curation, Investigation, Writing – original draft. Amir Almasi-Hashiani: Methodology, Formal analysis, Writing – review & editing. Sharareh Eskandarieh: Project administration, Resources, Supervision, Validation, Writing – review & editing. Mohammad Ali Sahraian: Conceptualization, Project administration, Resources, Supervision, Validation, Writing – review & editing.
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Abbasi Kasbi, N., Ghane Ezabadi, S., Kohandel, K. et al. Lifetime exposure to smoking and substance abuse may be associated with late-onset multiple sclerosis: a population-based case-control study. BMC Neurol 24 , 327 (2024). https://doi.org/10.1186/s12883-024-03815-9
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