People living with HIV (PLWH) experience a disproportionate burden of mental health problems compared to people living without HIV. This systematic review aims to depict the spectrum of resilience resources that may promote the mental health of PLWH at the individual, interpersonal, organisational, community and policy levels. A systematic literature search was conducted in PsycINFO, Scopus, Medline and advanced Google Scholar. The quality of included studies was assessed using the Mixed Methods Appraisal Tool (MMAT). Of the 591 studies identified, fourteen were included representing a total of 5,142 PLWH from China, Ghana, Nepal, Spain, Tanzania and the USA. Resilience resources were identified at the individual level (self-efficacy, self-esteem, acceptance, hope, optimism, religiosity/spirituality, belief in fate, mindfulness, strength and self-responsibility); interpersonal level (social support and parental monitoring); and community level (attending HIV clinic support groups and access to healthcare). All quantitative studies were cross-sectional, limiting inferences about causation or directionality. Future research should focus on resilience resources at the organisational and policy levels and incorporate longitudinal designs.

ObjectivesWe investigated whether UK military personnel exposed to sarin during the ‘Service Volunteer Programme’ at Porton Down had increased rates of mortality or cancer incidence over a 52-year follow-up.MethodsA historical cohort study assembled from UK military records, comprising male veterans exposed to sarin during the ‘Service Volunteer Programme’ at Porton Down, UK (n=2975) and a comparison group of similar veterans who did not attend (n=2919). Mortality and cancer incidence data were obtained from national registries up to December 2019. Analysis was conducted using Cox regression adjusted for age, year of birth and service characteristics.ResultsOver a median follow-up of 52.2 years (range 2 days to 74.6 years), 1598 (53.7%) sarin-exposed veterans and 1583 (54.3%) non-exposed veterans died. Adjusted HRs for all-cause mortality were raised for any sarin exposure (HR=1.08, 95% CI 1.01 to 1.16), two or more exposures (HR=1.25, 95% CI 1.04 to 1.49) and higher doses (air >15 mg.min/m3) (HR=1.15, 95% CI 1.02 to 1.30). For cause-specific mortality, sarin exposure was associated with deaths from ‘other’ circulatory diseases (excludes ischaemic and cerebrovascular diseases) (HR=1.41, 95% CI 1.06 to 1.87) and alcohol-attributable deaths (HR=2.66, 95% CI 1.40 to 5.07). There was no association between sarin exposure and overall cancer incidence (HR=1.01, 95% CI 0.93 to 1.10), but cancer incidence was higher for alcohol-related neoplasms (HR=1.24, 95% CI 1.01 to 1.51).ConclusionsSarin exposure was associated with increased rates of mortality over a 50-year follow-up. The strongest associations were observed for deaths attributable to alcohol and ‘other’ circulatory diseases.

Background We investigated whether military personnel involved in chemical warfare agent research at Porton Down had increased rates of mortality or cancer incidence. Methods This was a historical cohort study comprising male UK veterans who participated in the 'Service Volunteer Programme', 1941-89, identified from Porton Down experiment books, and a comparison group of similar 'non-Porton Down' veterans identified from military personnel files. Of 19 233 records retrieved for each group, 18 133 (94%) Porton Down and 17 591 (92%) non-Porton Down were included in our analytical sample. Mortality and cancer incidence data were obtained from national registries up to December 2019. Results Over a median follow-up of 48.1 years, 10 935 Porton Down veterans (60.3%) and 10 658 non-Porton Down veterans (60.6%) had died. After adjustment for age, year of birth and military service characteristics, overall, Porton Down veterans had a 6% higher rate of all-cause mortality compared with non-Porton Down veterans [hazard ratio (HR) = 1.06, 95% confidence interval (CI) 1.03-1.09]. For cause-specific mortality, Porton Down veterans had higher rates of death from genitourinary diseases (HR = 1.34, 95% CI 1.05-1.70) and deaths attributable to alcohol (HR = 1.44, 95% CI 1.07-1.94), with weaker associations observed for deaths from infectious and parasitic diseases (HR = 1.32, 95% CI 0.99-1.78), lung cancer (HR = 1.10, 95% CI 1.01-1.20) and external causes (HR = 1.15, 95% CI 1.00-1.32). Associations with all-cause mortality were stronger for veterans who attended Porton Down between 1960 and 1964 (HR = 1.34, 95% CI 1.19-1.50); likelihood-ratio test, P = 0.006. There was no association between attendance at Porton Down and overall cancer incidence (HR = 1.00, 95% CI 0.95-1.03). Conclusions Overall, mortality rates were slightly higher in Porton Down veterans, but there was no difference in cancer incidence. Associations for mortality were stronger in Porton Down veterans who attended in the early 1960s.

The Porton Down Veterans cohort was established to address concerns raised by former service personnel that their long-term health may have been affected due to their involvement in chemical experiments as part of the ‘Service Volunteer Programme’ at Porton Down, Wiltshire, UK, between 1941 and 1989. In 2001, the Medical Research Council (MRC) and UK Ministry of Defence funded an independent epidemiological study led by researchers at the University of Oxford to examine whether service personnel who attended Porton Down had different rates of mortality or cancer incidence compared with service personnel who did not attend Porton Down. In 2018, the MRC awarded further funding for a second phase led by the King’s Centre for Military Health Research, King’s College London, UK. The primary aim was to reexamine the original research questions with 15 years of additional cancer and mortality registration data, and the secondary aim was to explore additional uses of the cohort. For England and Wales, ethics approval for the most recent phase of the study was granted by the Research Ethics Service Committee (14/LO/1760) and the Health Research Authority’s Confidentiality Advisory Group (CAG; 18/ CAG/0171) under section 251 of the National Health Services Act 2006. For Scotland, approval was granted by the Public Benefit and Privacy Panel for Health and Social Care (PBPP-HSC). Data Sharing Agreements are in place with NHS Digital and the PBPP-HSC, which are reviewed annually.

Background and aim: To investigate whether veterans involved in chemical warfare agents research at Porton Down have increased rates of mortality or cancer incidence. Methods: The study is a historical cohort study. Participants are male UK veterans who participated in the 'Service Volunteer Programme', 1941-1989, identified from Porton Down experiment books, and a comparison group of similar 'non-Porton Down' veterans identified from military personnel files. Of 19,233 records retrieved for each group, 18,069 (94%) Porton Down and 17,588 (91%) non-Porton Down are included herein our study sample. The main outcome measures – National Health Service Central Registry Data on mortality and cancer registrations up to December 2019. Results: Over a median follow-up of 48.1 years, 10,889 Porton Down veterans (60.3%) and 10,657 non-Porton Down veterans (60.6%) died. After adjustment for age, year of birth, and military service characteristics, overall, Porton Down veterans had a 7% higher rate of all-cause mortality compared to non-Porton Down veterans. Associations with all-cause mortality were stronger for veterans who attended Porton Down between 1960 and 1964 (1.36, 95% CI 1.20 to 1.54), compared to other periods; likelihood-ratio test, p=0.006. For cause-specific mortality, Porton Down veterans had a statistically significantly higher rates of death from infectious and parasitic disease (5%), genitourinary (45%), circulatory diseases (5%), external causes (23%) and deaths attributable to alcohol (48%). There was no association between attendance at Porton Down and overall cancer incidence (0.99, 0.95 to 1.03). although Porton Down veterans had higher rates of neoplasms of 'uncertain or unknown behaviour' (1.26, 1.04 to 1.53), but lower rates of 'other urinary tract' neoplasms (0.77, 0.60 to 0.98). Conclusions: Overall, mortality rates were slightly higher in Porton Down veterans, but there was no difference in cancer incidence. Associations were stronger in Porton Down veterans who attended in the early 1960s.

Key PointsQuestionHow are affective symptoms over the life course associated with mortality? FindingsIn a British birth cohort (n=3001), affective symptoms were assessed between adolescence and age 53 years. Those who had case-level affective symptoms 1, 2, and 3 to 4 times had 76%, 87%, and 134% higher rates of premature mortality, respectively, by age 68 years compared with those who never experienced case-level symptoms; associations were largely explained by factors in adulthood, such as self-reported health conditions, smoking, and physical activity. MeaningFuture research into causal pathways and potential points of intervention for premature mortality should consider affective symptom history. ImportanceAssociations between affective symptoms and mortality have been evaluated, but studies have not examined timing or cumulative exposure to affective symptoms over the life course. ObjectivesTo examine how lifetime accumulation and timing of affective symptoms are associated with mortality and identify potential explanatory factors. Design, Setting, and ParticipantsData were obtained from the MRC National Survey of Health and Development (1946 British birth cohort), a socially stratified, population-based sample originally consisting of 5362 singleton births in England, Wales, and Scotland during March 1946. The cohort has been followed up 24 times, most recently in 2014-2015. Eligible participants included those flagged for mortality with affective symptom data available at a minimum of 3 time points (n=3001). Data analysis was conducted from July 2016 to January 2019. ExposuresAffective symptoms were assessed at ages 13 to 15 years (teacher-rated questionnaire), 36 years (Present State Examination clinical semistructured interview), 43 years (Psychiatric Symptom Frequency questionnaire), and 53 years (General Health Questionnaire-28). Case-level affective symptoms were determined by those scoring in the top 16th percentile (ie, suggestive of a clinical diagnosis). Main Outcomes and MeasuresMortality data were obtained from the UK National Health Service Central Register from age 53 to 68 years. ResultsOf 3001 study members (1509 [50.3%] female, 1492 [49.7%] male), 235 individuals (7.8%) died over a 15-year follow-up. After adjustment for sex, those who experienced case-level affective symptoms 1, 2, and 3 to 4 times had 76%, 87%, and 134% higher rates of premature mortality, respectively, compared with those who never experienced case-level symptoms. Case-level symptoms in adolescence only (ages 13-15 years) were associated with a 94% increased rate of mortality, which was unexplained after full adjustment for covariates (hazard ratio, 1.73; 95% CI, 1.10-2.72). Associations between participants with case-level symptoms multiple (2-4) times and mortality were predominately explained by adult health indicators and behaviors. For example, associations for those with case-level symptoms 3 to 4 times were most strongly attenuated by number of health conditions (32.1%), anxiolytic use (28.4%), lung function (24.6%), physical activity (23.9%), smoking (24.6%), antidepressant use (20.1%), diet (16.4%), pulse rate (12.7%), and adult social class (11.2%). Conclusions and RelevanceLifetime accumulation of affective symptoms may be associated with an increased rate of mortality, with explanatory pathways dependent on the duration and timing of symptoms. Future research into causal pathways and potential points of intervention should consider affective symptom history. This cohort study examines mortality in individuals with varying levels of affective symptoms occurring over 15 years.

Comparisons between cohort studies and nationally representative ‘real-world’ samples are limited. The NCDS (1958 British birth cohort) follows those born in Britain in a single week in March 1958 (n=18,558); and the ONS Longitudinal Study (LS) contains linked census data and life events for a 1% sample of the population of England and Wales (> 1 million records; allowing for sub-samples by age, ethnicity, or other socio-demographic factors). Common country-and age-matched socio-demographic variables were extracted from the closest corresponding time-points, NCDS 55-year survey in 2013 (n=8107) and LS respondents aged 55 in 2011 (n=7052). Longitudinal associations between socio-demographic exposures (from the NCDS 46-survey in 2004 and LS respondents aged 45 in 2001) and long-term limiting illness (from NCDS 2013 and LS respondents 2011, aged 55) were assessed using logistic regression. The NCDS 55-year sample had similar characteristics to LS respondents aged 55 for sex and marital status, but the NCDS sample had lower levels of long-term limiting illness (19.7% vs 22.8%), non-white ethnicity (2.1% vs 11.7%) and living in South England (46.9% vs 50.1%), and higher levels of full-time employment (61.2% vs 55.2%), working in professional/higher managerial occupations (35.7% vs 29.2%), and living with a spouse (69.1% vs 64.9%), all p<0.001. Nevertheless, longitudinal associations between socio-demographic exposures and long-term limiting illness were similar in the NCDS and LS samples (all tests of between-study heterogeneity in mutually adjusted models p>0.09) suggesting these NCDS findings are largely generalisable to the population of England and Wales.

IntroductionAn update to the Porton Down Veterans Cohort study is planned for 2018–2021.BackgroundChemical warfare agents continue to be deployed by rogue states and terrorists, e.g. in Syria, Iraq, Tokyo, and Salisbury UK, yet their impact on long-term health is largely unknown. The Porton Down cohort comprises of 18 276 men who took part in the ‘human volunteer programme’ of chemical warfare agent research at Porton Down, UK, between 1941 to 1989, and a comparison group of 17 600 men who also served in the military. An original study linked veterans’ records to national registry data on cancer incidence and mortality up to 2004. By the end of 2004, 7306 of the Porton Down veterans and 6900 of the comparison cohort had died. The results showed Porton Down veterans had no overall excess of cancers (rate ratio (RR)=1.00, 95% CI 0.95–1.05) and a small (6%) excess of all-cause mortality (RR=1.06, 1.03–1.10) when compared with non-Porton Down veterans. Porton Down veterans had higher rates of certain cancers (e.g. ill-defined malignant neoplasms, andin situneoplasms) and specific causes of death (e.g. genitourinary, circulatory and external causes).ObjectivesThe updated study aims to replicate the original analyses but with an additional 15 years of follow-up – estimated to increase the number of deaths available for study to c 22 200. This will improve statistical power, allowing exposures and outcomes of interest from prior literature to be examined at a level of detail not possible in the original study, e.g. nerve agent antidotes, riot control agents, neurological mortality, and rarer cancers.ImplicationsGreater understanding of the long-term risks associated with exposure to chemical agents could lead to raised awareness among policy makers and health care providers, leading to improved diagnosis and quality of care.Conflict of interestNone

An occupational cohort study is the most robust epidemiological design for studying the effects of workplace hazards and the findings can be extended to the general environment. A cohort may be time-consuming, expensive, and labour-intensive to set up but, once done, it can be extended forward in time, as well as laterally to incorporate new outcome variables, and it can also support nested case-control studies. It is therefore important that the human and material investment is preserved so that these valuable resources can be fully exploited. In recent years, the bureaucratic burden on researchers in many countries has increased. In the UK, for example, research ethics, data protection, and data access application procedures have become more cumbersome, with an increase in the number of supporting documents required from researchers. Although fast-track procedures exist, epidemiological studies often require the same formal procedures and oversights as more invasive and potentially dangerous physiological and pharmacological studies. Fortunately, there are now initiatives which support occupational cohort studies. The UK Medical Research Council (MRC), for example, published in 2014 a review and guidance about maximising the value of UK population cohorts and it has also set up a Cohort Strategic Review Group to pre-assess funding applications for new cohorts and for updates to existing cohorts (http://mrc.ukri.org). As another example, OMEGA-NET has been set up to ‘create a network to optimize and integrate occupational, industrial, and population cohorts at the European level’ (http://omeganetcohorts.eu/). We propose that a checklist be defined for assessment of research protocols for new cohorts or updates to existing cohorts, in order to assist official committees in their work and streamline the approval process for both researchers and committees. EPICOH would be well-placed to draft and promulgate such a checklist, working with interested organisations, such as OMEGA-NET and the UK MRC.

OBJECTIVE:Sleep disturbance is a known risk factor for depression, but it is not known whether sleep disturbance contributes to greater risk of depression in those infected with human immunodeficiency virus (HIV+) as compared to those uninfected with HIV (HIV-). METHODS:Using data from the Multicenter AIDS Cohort Study, a population-based prospective study of men who have sex with men (MSM), self-reported sleep disturbance (>2 weeks) and depressive symptoms (Clinical Epidemiologic Scale for Depression, CES-D) were assessed every 6 months over 12 years of follow-up. Adjusted mixed effects logistic regression analyses tested whether sleep disturbance predicted depression (CES-D ≥ 16) at the immediate subsequent visit, and so on over 12 years, in non-depressed HIV+(N = 1054; 9556 person-visits) and non-depressed HIV- (N = 1217; 12,680 person-visits). In HIV+ vs. HIV- MSM, linearly estimated average incidence of depression and normalized cumulative rate of depression over 12 years were compared. RESULTS:In the HIV+ MSM, sleep disturbance was associated with a significant increase in depression 6 months later (OR = 1.6; 95% CI, 1.30, 1.96), which was significantly greater (P < .05) than in HIV- MSM (OR = 1.16; 95% CI, 0.94, 1.44). HIV status and sleep disturbance interacted (P < .001), such that incidence of depression and normalized cumulative rate of depression were greater in HIV+ with sleep disturbance than in HIV+ without sleep disturbance and HIV- groups (all P's < 0.001). CONCLUSIONS:HIV+ persons who report sleep disturbance represent a high risk group to be monitored for depression, and possibly targeted for insomnia treatment to prevent depression. FUND: National Institute of Allergy and Infectious Diseases.

BackgroundLittle is known about the relationship between adolescent affective problems (anxiety and depression) and mortality.AimsTo examine whether adolescent affective symptoms are associated with premature mortality, and to assess whether this relationship is independent of other developmental factors.MethodData (n= 3884) was from Britain's oldest birth cohort study – the National Survey of Health and Development. Adolescent affective symptoms were rated by teachers at ages 13 and 15 years: scores were summed and classified into three categories: mild or no, moderate and severe symptoms (1st–50th, 51st–90th and 91st–100th percentiles, respectively). Mortality data were obtained from national registry data up to age 68 years. Potential confounders were parental social class, childhood cognition and illness, and adolescent externalising behaviour.ResultsOver the 53-year follow-up period, 12.2% (n= 472) of study members died. Severe adolescent affective symptoms were associated with an increased rate of mortality compared with those with mild or no symptoms (gender adjusted hazard ratio 1.76, 95% CI 1.33–2.33). This association was only partially attenuated after adjustment for potential confounders (fully adjusted hazard ratio 1.61, 95% CI 1.20–2.15). There was suggestive evidence of an association across multiple causes of death. Moderate symptoms were not associated with mortality.ConclusionsSevere adolescent affective symptoms are associated with an increased rate of premature mortality over a 53-year follow-up period, independent of potential confounders. These findings underscore the importance of early mental health interventions.Declaration of interestNone.

Background Child maltreatment (abuse and neglect) has established associations with mental health; however, little is known about its relationship with physical functioning as few studies have been undertaken. Physical functioning in adulthood is an important outcome to consider, as it is strongly associated with an individual's ability to work, and future disability, dependency, hospitalisations and mortality. We aimed to establish whether maltreatment was associated with physical functioning, independent from other early-life adversities. Methods Using data from the 1958 British birth cohort (n=8150), we examined associations between child neglect and physical, psychological, witnessing and sexual abuse with physical functioning at age 50. Poor physical functioning was defined by those scoring <65 on the Short-Form 36 (SF-36) Physical Functioning scale. We also examined two secondary outcomes – mental health and self-reported health at age 50. Associations between each maltreatment and outcome were assessed using logistic regression with and without adjustment for covariates, including childhood social class, birthweight, childhood health, parental chronic illness, and parental education. Results 23% of participants reported at least one type of maltreatment and 12% were identified with poor physical functioning. Neglect, psychological, and sexual abuse were associated with poor physical functioning independent of all covariates and other maltreatments: ORadj1.55 (95% CI 1.24–1.93), 1.49 (1.17–1.88) and 2.56 (1.66–3.96), respectively. Odds of poor physical functioning increased with multiple types of maltreatment; ORadj ranged from 1.49 (1.23–1.82) for a single type to 2.09 (1.53–2.87) for those reporting >3 types of maltreatment, compared to those with none. Associations of comparable magnitude were observed for mental and self-reported health outcomes; e.g. ORadj varied between 1.42–1.55 for neglect across the three adult outcomes. Conclusion Child neglect, psychological, and sexual abuse were associated with poor physical functioning at 50 years, with accumulating risk for those with multiple types of maltreatment. To our knowledge, we are the first to demonstrate that these associations are independent of numerous early-life adversities, and comparable in magnitude to those observed for mental health and self-rated health. Our findings underscore the importance of the prevention of maltreatment and the alleviation of its ill-effects to promote healthy ageing.

Objective Child maltreatment (abuse and neglect) has established associations with mental health; however, little is known about its relationship with physical functioning. Physical functioning (ie, the ability to perform the physical tasks of daily living) in adulthood is an important outcome to consider, as it is strongly associated with an individual’s ability to work, and future disability and dependency. We aimed to establish whether maltreatment was associated with physical functioning, independent of other early-life factors. Setting 1958 British birth cohort. Participants 8150 males and females with data on abuse and who participated at age 50 years. Outcome measures The primary outcome was poor physical functioning at 50 years (<65 on the Short-Form 36 survey physical functioning subscale). Secondary outcomes included mental health and self-reported health at 50 years. Results 23% of participants reported at least one type of maltreatment; 12% were identified with poor physical functioning. Neglect (ORadj 1.55, 95% CI 1.24 to 1.93), psychological abuse (ORadj 1.49, 1.17–1.88) and sexual abuse (ORadj 2.56, 1.66–3.96) were associated with poor physical functioning independent of other maltreatments and covariates, including childhood social class, birth weight and childhood illness. Odds of poor physical functioning increased with multiple types of maltreatment (ptrend <0.001); ORadj ranged from 1.49 (1.23–1.82) for a single type to 2.09 (1.53–2.87) for those reporting > 3 types of maltreatment, compared with those with none. Associations of similar magnitude were observed for mental and self-reported health outcomes. Conclusions Child neglect, psychological and sexual abuse were associated with poor physical functioning at 50 years, with accumulating risk for those with multiple types of maltreatment. Associations were independent of numerous early-life factors and were comparable in magnitude to those observed for mental health and self-rated health. Prevention or alleviation of the ill effects of maltreatment could be an effective policy intervention to promote healthy ageing.

Objective: To explore the association between depressive symptom history and cancer incidence.Methods: Affective/emotional depressive symptoms were assessed using the General Health Questionnaire (GHQ-30) depression sub-scale across phase 1 (1985-1988), phase 2 (1989-1990), and phase 3 (1991-1994) of the Whitehall II prospective cohort study; 'chronic' = depressive episode at phase 1,2 and 3; 'new' = depressive episode at phase 3 only. Cancer incidence was obtained from the National Health Service Central Register with an average follow-up of 15.6 years (range 0.08-17.4). The study sample consisted of 6983 participants, aged 35-55 years at baseline.Results were adjusted for age, sex, socio-economic position, health behaviours, health status/conditions, medication, and social support. Results: Over a 17.4 year follow-up, chronic depressive symptoms did not increase the risk of cancer incidence compared to those who never experienced symptoms (hazard ratio (HR) = 1.03, 95% confidence interval (CI): 0.71-1.49). Participants who experienced new depressive symptoms had an increased risk of cancer incidence in the first 9 years of follow-up (HR = 1.89, 95% Cl: 123-2.90) but no increased risk in later years (HR = 0.84, 95% CI: 0.52-135).Conclusion: Chronic depressive symptoms were not associated with cancer incidence. In contrast, new-onset symptoms were associated with a substantially increased risk, possibly due to reverse causality. (C) 2015 Elsevier Inc. All rights reserved.

Background Despite accounting for nearly half of all ill-health in those aged under 65, and 23% of the total UK burden of disease, mental health receives only 13% of NHS expenditure. Moreover, these figures do not take into account the potential effect of mental health on physical morbidity. Several previous studies have shown an association between mental disorders and earlier mortality; however the relationship remains largely unexplained. This study will establish whether there is an association between psychiatric symptoms and premature mortality, and if so, whether this relationship can be explained by a range of potential mediators and confounders. Methods In the nationally representative prospective 1946 British birth cohort study, psychiatric symptoms were assessed at age 36 (1982) using the Present-State-Examination, a clinically validated interview; symptoms were coded according to an index-of-definition into 'none', 'mild' or 'severe'. Mortality was obtained from the National Health Service Central Register until end of May 2012, an average follow-up of 29.4 years. The study sample consisted of 3305 participants, of which there were 343 deaths. Covariates included measures of adult and childhood socio-economic position, health behaviours, physical health function, and social networks. Stata 12 was used to perform all analyses. Multiple-imputation was used for missing covariate data, and Cox regression was used to estimate hazard ratios. Results After adjustment for sex, 'severe' psychiatric symptoms appeared to increase the risk of all-cause mortality by 50% compared to those who had no symptoms (HR=1.50, 95% CI 1.14–1.98). After full adjustment for covariates, this effect was no longer statistically significant (HR=1.20, 0.89–1.61). The association was partially explained by smoking, pulse rate, marital status, and frequency of contact with friends. Excluding violent deaths and suicides led to similar results. An almost identical trend was observed with respect to cancer mortality. Conclusion Severe psychiatric symptoms in adulthood appear to increase the risk of premature mortality. This effect may be partially explained by smoking, social networks, and physical health function. Quantifying the effect of mental health on mortality could help influence policy regarding NHS expenditure, whilst establishing potential pathways between psychiatric symptoms and mortality may highlight effective points of intervention.